Introduction

Cancer is a disease characterized by the abnormalities in the regulation of cell proliferation and differentiation. Many factors contribute to cancer development including genetics,1 lifestyle, and environmental carcinogens, among others.2 Cancer is the second leading cause of death worldwide after cardiovascular disease, accounting for 9.6 million deaths in 2018 according to data from the International Agency for Research on Cancer. Lung cancer is the leading cause of cancer death (18.4%), followed by breast cancer (11.6%), and prostate cancer (7.1%).3 Clinical manifestations include pain, bleeding, lumps and ulcers at the site of disease, along with systemic symptoms such as weight loss and fatigue leading to cachexia. Traditional treatment modalities including surgery, radiotherapy, and chemotherapy have various disadvantages and cause side effects that are in some cases severe. Immunotherapies such as blockade of programmed death (PD)-1 and programmed death ligand 1 (PD-L1) immune checkpoints; chimeric antigen receptor T cell immunotherapy (CAR-T); using the monoclonal antibody against cancer antigen; and cytokine therapy offer a promising alternative to the conventional treatment approaches for cancer.4 In particular, cytokine therapy has shown encouraging results in both basic and clinical research settings.5

Cytokines are small proteins produced by various cells (immunocytes and non-immunocytes) as molecular messengers to communicate with each other or with other cells. Cytokines have versatile roles in several steps of the cancer immunity cycle including cancer antigen presentation, T cell priming and activation, effector T cell infiltration in cancer site, and cancer cell death, as shown in Figure 1. More importantly, cytokine-mediated signaling pathways control the direction of nave CD4+ T cell differentiation and thus determine the effects of anticancer immunity (Figure 2 and Table 1). Briefly, transforming growth factor (TGF-) signaling in nave CD4+ T cells is required for the differentiation of regulatory T cells (Tregs) and T helper type 17 (Th17) cells, both of which promote tumor progression. Additionally, Th17 cell differentiation and clonal expansion require a cocktail of cytokines (IL-6, IL-21, IL-23, IL-1, and TGF-).610 IL-17 secreted by Th17 cells guides macrophages and neutrophils to cancer sites and induces cancer-promoting inflammation. Th17 cells themselves also exert antitumor effects in the melanoma microenvironment by potentiating the functions of CD8+ T cells and T helper type 1 cells (Th1 cells).11 IL-10, IL-11, IL-4, and IL-13 are critical for the differentiation and development of T helper type 2 cells (Th2 cells),1217 whereas IL-12, IL-18, IL-1, and interferon (IFN)- promote Th1 cell development and activity.1823 Th1 cells modulate tumor-suppressing pathways by stimulating IFN- secretion and enhancing the cytotoxicity of natural killer (NK) cells and CD8+ T cells, while Th2 cells inhibit the anticancer immune responses by blocking Th1 cell differentiation and the release of IFN-. Vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)- promote cancer progression by directly facilitating angiogenesis, although recombinant TNF- has been shown to enhance the effect of combined chemotherapy regimens by increasing the permeability of tumor blood vessels.2427

Figure 1 Cytokines in the cancer immunity cycle.6 1) Antigens from dead cancer cells are captured by APCs, mainly by DCs. 23) DCs present cancer antigens to T cells to prime the adaptive immune response. 45) Activated effector T cells infiltrate cancer cells and then 6) kill cancer cells. Dead cancer cells release cancer antigens to continue the immune cycle. Cytokines that have been shown to promote or inhibit the anticancer immune responses are highlighted.

Abbreviations: IFN, interferon; IL, interleukin; TGF-, transforming growth factor ; TNF, tumor necrosis factor.

Figure 2 Varied roles of cytokines involved in anticancer immunity. Different cytokines determine nave CD4+ T cell fate to Tregs, Th17, Th1 or Th2, and further regulate anticancer immunity. IL-12, IL-18, IL-1, IL-10 and IL-11 secreted by dendritic cells (DCs) drive Th1 or Th2 cell differentiation. TGF-, IL-11, IL-6, and IL-21 are important signals for Treg and Th17 cell differentiation. IFN-, IL-2, IL-15, and IL-7 secreted by Th1 cells enhance the anticancer effects of cytotoxic T lymphocytes, NK cells, B cells, and macrophages, which can be suppressed by IL-4, IL-13, and IL-10 secreted by Th2 and Treg cells. IL-17 secreted by Th17 cells play a role in the induction of cancer-promoting anticancer inflammation by MDSCs. VEGF and TNF- promote cancer progression by facilitating angiogenesis. Cytokines functions are shown in text boxes; those that promote anticancer immunity are in red while those that inhibit anticancer immunity are in black.

Because the roles of cytokines are diverse and precise applications of cytokines are greatly needed, it is urgent to update the progresses of cancer immunotherapy with cytokines. Here, we review total 2339 clinical trials using or by targeting cytokines for precise treatment of cancers registered with ClinicalTrials.gov; summarize the therapeutic efficacy of typical cytokines based on clinical data; and highlight progress in the development and application of nanomaterials for cytokine-based therapy.

In order to review clinical application of cytokines in cancer therapy, we have searched all the known cytokines in ClinicalTrials.gov. In the advanced search page of ClinicalTrials.gov, we entered cytokine name, such as IL-2, in other term section and chose completed in the recruitment status section. Then, we download the search results and screen the trials item by item to make sure that the intervention of the trial includes cytokine-based drugs and the condition of the trial is cancer. As a result, we got 25 cytokines with clinical trials that had completed recruitment in ClinicalTrials.gov, and we also checked 2 cytokines (IL-10 and IL-17) without published clinical studies for cancers because of their crucial roles in anticancer immunity. Finally, we screen out 2630 clinical trials using cytokines as either therapeutic agents or targets in treating cancers registered with ClinicalTrials.gov that had completed recruitment up to January 2021.

It is interesting that G-CSF, GM-CSF, VEGF, IL-2 and IFN- are the five most studied cytokines (Figure 3A and Supplementary Table 1), which could be explained by the fact that they have been discovered and clinically studied very early (Figure 4A and B) and they play very important roles in cancer treatment. VEGF is the most studied target for the treatment of most types of cancer because the role of VEGF in angiogenesis induction, cell proliferation and promoting vascular permeability is extremely important for cancer growth, migration and infiltration. CSF can promote proliferation and differentiation of multiple immune cells such as macrophage, granulocytes, and mononuclear phagocytes, and thus is widely used as medication to stimulate the production of white blood cells following chemotherapy. Similarly, IL-2 is used to stimulate T cell production for enhancing anti-cancer immunity. IFN- can directly inhibit tumor cell proliferation and augment anti-tumor immunity by promoting MHC expression, antigen presentation, and the function of tumor-infiltrating Th1 cells, CTLs and macrophages. The clinical trials of cytokines cover nearly all cancer types (Figure 3B) but most of the clinical trials are done on melanoma and hematological malignancies because the two cancer types have better responses and outcomes than other cancers in the immune therapy.28,29

Figure 3 Clinical research status of cytokines. Number of cancer clinical trials using cytokine-based drugs treating all cancer types (A) or each cancer type (B) registered with ClinicalTrials.gov as of January 2021.

Figure 4 Historical timelines of cytokine research. (A) Timeline of cytokine discovery. The time point is the year in which the cytokines, EPO,69 IFNs,70,71 EGF,72 G-CSF,73,74 FGF,75 IL-1,76 IL-2,77 IGF,78 TNF,79 GM-CSF,80 TGF-,81 IL-3,82 IL-4,83 IL-6,84 IL-7,85 IL-10,86 IL-12,87 IL-13,88 VEGF,89 IL-11,90 IL-15,91 IL-17,92 IL-18,93 IL-21,94,95 and CCL21,96,97 were first described. (B) Timeline of the first clinical trials of cytokines for cancer treatment. The time point is the year that the trial was first registered with ClinicalTrials.gov. Clinical trial registry (NCT) numbers are shown.

The year of discovery of each cytokine and the year of the first clinical trial with the cytokine for cancer treatment are shown, respectively, in Figure 4A and B, which gives a visualized understanding of research progresses of cytokines in certain years. The main cytokines were discovered in the last 3 decades of last century and the clinical trials were carried out intensively between 1998 and 2008. The interval time from the discovery to the first clinical trial of certain cytokine is varied with the maximum of 95 years (EPO) and minimum of 7 years (IL-21). The cytokine-based drugs could be grouped into two types: cytokine drugs and drugs targeting cytokines.

IL-2, type I IFN, IL-12, chemokine (C-C motif) ligand (CCL) 21, and colony-stimulating factors (CSF) family cytokines are known to promote anticancer immunity. Although IFN-, TNF-, and IL-1 families play a dual role in the cancer immunity cycle, they are widely studied for their anticancer activity. In this section, we present the efficacy of these cytokine-based drugs in cancer treatment.

There are 268 trials registered with ClinicalTrials.gov using IL-2 for cancer treatment. Of the 52 trials for which results are available, 7 treated cancer with IL-2 alone, including 3 trials using IL-2 and 4 using IL-2 derivatives (hu14.18-IL12, denileukin diftitox [ONTAK], and ALT-801) for the treatment of melanoma, breast cancer, metastatic renal cell carcinoma (mRCC), and neuroblastoma. There were 45 trials investigating the effects of IL-2 combined with other therapies. In general, melanoma and leukemia responded better than other types of cancer to IL-2 treatment and IL-2 performed more outstanding when combined with other therapies in cancer treatment. The objectives of clinical studies using IL-2 in cancer treatment are summarized in Figure 5.

Figure 5 Application of IL-2 in 52 clinical trials for cancer therapy. IL-2 has been used in combination with lymphocytes, NK cells, genetically engineered cells, monoclonal antibodies, and tumor antigens as well as with radiotherapy, chemotherapy, and chemoradiotherapy. Dose finding, selected studies, and effects of recombinant IL-2 are shown. Numbers in parentheses are the number of clinical trials.

In 1992, high-dose aldesleukin became the first cytokine approved by the US Food and Drug Administration (FDA) for the treatment of mRCC based on an objective response rate (ORR) of 14% in 255 patients.30 In 2006, a new trial using high-dose aldesleukin for the treatment of mRCC was conducted by the Cytokine Working Group to evaluate the clinical utility of PD-L1, B7 homolog 3 protein, carbonic anhydrase 9, plasma VEGF, and fibronectin levels as biomarkers for therapeutic response monitoring. PD-L1 and B7 homolog 3 protein were identified as candidate markers but require independent validation.31 The IL-2 derivative hu14.18-IL-2, which consists of 2 molecules of IL-2 covalently linked via the Fc region, has demonstrated long-term tumor control in animal models.32 In Phase I and II trials, hu14.18-IL-2 prolonged the tumor-free survival period in some patients with recurrent stage III or stage IV melanoma following resection.33

The anticancer efficacy of IL-2 may be enhanced when it is used in combination with other immunotherapies and chemotherapy agents. In one trial, 6 of 11 patients with non-Hodgkin lymphoma treated with IL-2 plus rituximab achieved complete or at least partial remission (NCT00994643). A Phase III trial reported that IL-2 combined with other immunotherapeutic reagents, including dinutuximab and granulocyte/macrophage (GM)-CSF, enhanced the efficacy of isotretinoin in the treatment of neuroblastoma after stem cell transplantation; the 3-year event-free survival rates for isotretinoin with and without immunotherapy is 62.9% against 48.1%, respectively (NCT00026312). Results from 3 other trials supported the survival benefits of combination treatment (NCT01334515, NCT01592045, and NCT01041638). In addition to immunotherapy, data from 27 trials suggest that chemotherapy drugs such as ONTAK, etoposide, cyclophosphamide can increase the antitumor activity of IL-2.

Given the therapeutic effects of IL-2, other members of the IL-2 family including IL-7, IL-15, and IL-21, that are known to act independently or synergistically with IL-2 in the anticancer immune response have been investigated for the treatment of breast cancer, renal cell cancer, melanoma, and leukemia. However, in a trial of IL-7 in patients with metastatic castration-resistant prostate cancer (NCT01881867), the number of T cells per 300,000 peripheral blood mononuclear cell was not higher than in the comparator group. In trials investigating the efficacy of intravenous (NCT01385423 [phase I]) or subcutaneous (NCT02395822 [phase II]) recombinant human IL-15 in enhancing the effects of NK cell therapy in patients with acute myelogenous leukemia, 32% of patients in the phase I trial and 40% of those in the Phase II trial achieved complete remission.34 In a phase II trial evaluating the efficacy and safety of IL-21 in the treatment of malignant melanoma (NCT01152788), IL-21 did not demonstrate a clinical benefit over dacarbazine, with a progression-free survival (PFS) of 1.87 vs 2.04 years, although IL-21 was associated with fewer adverse events.

Type I IFNs including IFN- and IFN- play an essential role in the presentation of cancer antigens by mediating the maturation and activation of dendritic cells (DCs) and inducing the expression of major histocompatibility complex I molecules on tumor cells.35,36 Since 1996, there have been 248 trials investigating the therapeutic potential of IFN- in the treatment of cancers including melanoma and leukemia, with results for 76 available on ClinicalTrials.gov. Although there is in vitro evidence that IFN- more potently inhibits tumor cell proliferation than IFN-, there have been no clinical trials demonstrating its efficacy in cancer therapy.

A study conducted from 1988 to 2010 evaluating the efficacy of high-dose IFN--2b in 1150 patients who had undergone resection for stage II or III melanoma (NCT00003641) found no improvements in 5-year relapse-free survival and overall survival (OS) rates. In addition to treating melanoma, IFN- has been used as first-line treatment for mRCC, but was found to be less effective than the tyrosine kinase inhibitor su011248 in a phase III trial (NCT00083889). Various forms of IFN- including pegylated (PEG)-IFN- and recombinant adenovirus (rAd)-IFN (encoding IFN-2b) have been evaluated in clinical studies. Two trials compared the efficacy of PEG-IFN- and IFN- in different types of cancer; in patients with melanoma, the median OS was 25.63 months with PEG-IFN- vs 20.67 months with IFN- (NCT03552549), whereas in chronic myelogenous leukemia, the 12-month survival rate was slightly higher in the IFN- group than in the PEG-IFN- group (91.3% [158/173] vs 90.1% [154/171]) (NCT03547154). In both trials, more severe adverse effects were reported in patients receiving PEG-IFN- treatment. In another phase II study (NCT01687244), rAd-IFN showed promising results in patients with Bacillus Calmette-Gurin-refractory or relapsed bladder cancer.

The antitumor activity of IFN- can be dramatically enhanced by including other types of immunotherapy in the treatment regimen. In a phase III trial initiated in 2004 (NCT00738530), 649 patients with mRCC received IFN- alone or with bevacizumab; PFS was 5.5 and 10.2 months, respectively, and ORR was 12.5% and 32.4%, respectively. When the chemotherapy drug vinblastine was added to the regimen, the PFS was increased to 274 days (NCT00520403). Results from 5 other trials supported the effects of IFN- in combination with bevacizumab. A trial assessing the efficacy of pembrolizumab (anti-PD-1) plus sylatron (PEGIFN--2b) for the treatment of advanced cholangiocarcinoma was initiated in 2017, but no patients completed the study due to adverse effects (NCT02982720).

As the sole type II IFN, IFN- is a typical pro-inflammatory cytokine that exerts antitumor effects by suppressing proliferation and promoting apoptosis in tumor cells and inducing necrotic death and inhibiting angiogenesis in tumors. However, IFN- was shown to upregulate PD-L1 expression on tumor cells, which suppressed anticancer immunity through the binding of PD-L1 to its receptor PD-1 on lymphocytes.23 Despite these conflicting roles in cancer, the therapeutic potential of recombinant or adenovirus-delivered IFN- is being investigated in 22 trials, although only 2 have posted results. In a phase II trial (NCT00501644), 59 patients with ovarian or fallopian tube cancer or primary peritoneal cancer were treated with subcutaneous GM-CSF and IFN- before and after intravenous carboplatin; the ORR was 56% and median time to progression was 6 months. However, there was no control group in this trial. Another phase II trial assessed the efficacy of IFN- combined with 5-fluorouracil (FU), leucovorin, and bevacizumab in patients with metastatic colorectal cancer (CRC) (NCT00786643), but the specific contribution of IFN- to the treatment effect was not investigated. In summary, the efficacy of IFN- in cancer therapy has yet to be established.

IL-12, which is mainly produced by antigen-presenting cells, plays an important role in regulating innate and adaptive immune responses. There are 47 registered Phase IIII trials evaluating the efficacy and safety of intratumoral IL-12 administration either alone (22 trials) or with other immunotherapies (eg, DCs, T cells, and vaccines; 17 trials) for the treatment of melanoma, Merkel cell carcinoma, ovarian carcinoma, head and neck squamous cell carcinoma, and other cancers. In most cases a plasmid encoding IL-12 was used. A phase III trial that enrolled 51 patients with melanoma optimized the therapeutic strategy (NCT01502293): patients underwent 5 treatment cycles at 3-month intervals consisting of 3 intratumoral injections of IL-12 plasmid immediately followed by in vivo electroporation, which resulted in an ORR of 32.1% higher than the other two groups (underwent 9 cycles [25.0%] and 2 cycles [25.0%] at 6-week intervals, respectively). On the other hand, tumor-infiltrating CD8+T cells expressing IL-12 showed unsatisfactory results for the treatment of metastatic melanoma in a phase I/II trial (NCT01236573).

TNF was initially recognized as an antitumor cytokine. However, endogenous TNF induces the expression of multiple cytokines that act on M2 macrophages to stimulate the extracellular matrix remodeling as well as the differentiation of myeloid endothelial progenitor cells, which promotes tumor angiogenesis.27 These findings suggest that TNF can serve as either therapeutic target or agent. The first clinical trial of TNF for cancer treatment was initiated in February 1992; to date, there have been 20 trials involving at least 1152 participants in which TNF or related biological agents were used to treat 3 main tumor typesnamely, melanoma, CRC, and head and neck cancer. Only one study has published results. Etanercept, a TNF inhibitor, was investigated for the treatment of idiopathic pneumonia in patients with leukemia and lymphoma after stem cell transplantation (NCT00309907), but the results did not reflect the effect of TNF inhibitor.

The anticancer efficacy of CSF family cytokines including GM-CSF, granulocyte (G)-CSF, erythropoietin (EPO), and IL-3, has been widely studied in clinical settings. To date, 1311 clinical trials enrolling over 200,000 cancer patients treated with GM-CSF and G-CSF alone or in combination have been registered at ClinicalTrials.gov; of these, 96% and 94% studied the effects of GM-CSF and G-CSF in combination therapy, respectively (Figure 6A).

Figure 6 The number and ratio of clinical trials of cytokine combined with other agents in cancer treatment. (A) Relative ratio of clinical trials using GM-CSF, G-CSF and VEGF receptor inhibitors alone or in combination. (B and C) Number of clinical trials using cytokine-based drugs alone or in combination.

EPO exhibits pro-proliferative and anti-apoptotic activities in multiple nonhematopoietic cell types including tumor cells.37 EPO has been used to alleviate cancer- and chemotherapy-related anemia. The first clinical trial of EPO for cancer treatment was initiated in 2003 and to date, 15 trials without results have been published at ClinicalTrials.gov.

IL-3, also known as multi-CSF and hematopoietic cell growth factor, has been the focus of 7 clinical trials. A single-arm trial study evaluating the efficacy of DT388IL3 fusion protein for the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes reported an overall response rate of 81.8% (NCT00397579).

IL-1 and IL-18 are members of the IL-1 family; IL-1 is an important regulator in innate immunity,38 and both cytokines stimulate IFN- production by T cells and NK cells. IL-1 has dual roles in anticancer immune response. Clinically, patients with high IL-1 concentrations in tumors have poor prognoses.39 Anakinra is an IL-1 receptor antagonist that is commonly used to treat rheumatoid arthritis; its antitumor efficacy has been assessed in 8 trials. In a phase II trial, anakinra combined with dexamethasone was used to treat multiple myeloma and plasma cell neoplasm (NCT00635154); the 6-month progression-free rate was 90.7%. 6 clinical trials are investigating a recombinant human IL-18, namely SB-485232, for the treatment of patients with melanoma, lymphoma, and ovarian neoplasms, but no results have been published.

Chemokines and their receptors mediate immunocytes trafficking into the cancer microenvironment, playing roles in promoting or inhibiting cancers. CCL21, together with CCL19, regulates the migration of DCs and T cells to secondary lymphoid organs when binding to their receptor CCR7, thus plays an important role in adaptive immunity and immune tolerance.40 Intratumoral injection of CCL21 enhances the infiltration of T cells and DCs in tumor.41 To date, 3 cancer clinical trials using CCL21 have been registered at ClinicalTrials.gov. In a phase II trial (NCT01433172), CCL21 combined with GM.CD40L vaccine (tumor antigen expressing GM-CSF and CD40L) was used to treat lung adenocarcinoma; the 6-month progression-free survival rate was higher in the combination group than in the GM.CD40L group (15.2% [5/33] vs 9.4% [3/32]).42 For chemokine (C-X-C motif) ligand (CXCL)12, CXCL8, CCL2, CCL3 and CCL5 which are involved in cancer progression and metastasis, few clinical trials studied drugs targeting their receptors, CXCR4, CXCR 1/2 and CCR2, and their effects for cancers have not been verified.43

TGF-, VEGF, epidermal growth factor (EGF), insulin-like growth factor (IGF) and broblast growth factor (FGF), IL-4, IL-13, IL-10, IL-6, IL-11, and IL-17 are known to inhibit anticancer immune response. In this section, we present efficacy of cancer therapy by targeting these cytokines.

TGF- is an oncogenic factor that facilitates evasion of systemic immune surveillance.44 The clinical efficacy of various inhibitors of TGF- signaling including GC1008 (fresolimumab, anti-TGF- monoclonal antibody), TEW-7197 (TGF- receptor activin-like kinase [ALK]4/ALK5), and AP 12009 (TGF-2 antisense oligodeoxynucleotide) has been investigated in metastatic breast cancer, RCC, recurrent or refractory high-grade glioma, and advanced melanoma. In a phase II trial examining the efficacy and safety of combined fresolimumab (1 or 10 mg/kg) and local radiotherapy in the treatment of metastatic breast cancer (NCT01401062), overall response rates were 100% with both low and high drug doses and the rate of serious adverse events was 27% and 25%, respectively. The results of 7 other trials of TGF- inhibitors in cancer treatment have yet to be reported.

Angiogenesis is a vital step in tumor progression and metastasis. Sustained expression of VEGF during tumor development induces the formation of tumor vasculature.45 Various VEGF receptor (VEGFR) inhibitors either alone or in combination with other drugs have been investigated for cancer treatment. These inhibitors include antibodies against VEGFR (eg, bevacizumab, ramucirumab, and ranibizumab); inhibitors of receptor protein kinases (eg, axitinib and vandetanib); soluble decoy receptors containing VEGFR domains (eg, aflibercept); and small molecules that interfere with the binding sites of VEGFR (eg, vatalanib). There are 301 trials registered at ClinicalTrials.gov for the treatment of various cancers (CRC, breast cancer, ovarian cancer, non-small-cell-lung cancer, lymphoma, etc) using VEGFR inhibitors, of which 35% have examined the effects of VEGFR inhibitor monotherapy (Figure 6A).

A large phase III clinical trial that enrolled 1690 participants investigated the efficacy of docetaxel alone or with vandetanib in non-small-cell-lung cancer (NSCLC) (NCT00312377). Median PFS was longer with the combination therapy than with docetaxel alone (17.3 vs 14 weeks), although median OS was comparable between the 2 groups (10.6 vs 10 months). In another phase III trial of 913 patients with NSCLC (NCT00532155), aflibercept increased the median OS of docetaxel from 10.05 to 10.41 months and prolonged median PFS from 4.11 to 5.19 months. In a phase III trial examining the efficacy of aflibercept vs a placebo in 1226 patients with metastatic CRC who had failed to respond to the FOLFIRI regimen (irinotecan, 5-FU, and leucovorin) (NCT00561470), median OS was increased from 12.6 to 13.5 months while median PFS was increased from 4.67 to 6.90 months. Besides combination with chemotherapy, the efficacy of VEGF inhibitors combined with other immunotherapies has been evaluated in 40 clinical trials. As described in the paragraph of IFN-, bevacizumab in conjunction with IFN- showed clinical benefits in mRCC and melanoma patients. Thus, VEGFR inhibition is an effective therapeutic strategy for the treatment of multiple cancers.

In addition to VEGF, growth factors such as EGF, IGF and FGF, have been shown to be crucial for the development and progression of certain cancers. Clinically, human epidermal growth factor receptor 1 and 2 (HER1 and HER2), IGF-1 receptor (IGF-1R) and FGF receptor (FGFR) have been found to be overexpressed in various cancers, particularly in breast and lung cancers.4648 There are 206, 71 and 14 trials for blocking EGFR, IGF-1R and FGFR, respectively, with small molecule inhibitors or monoclonal antibodies in treating cancers registered with ClinicalTrials.gov that had completed recruitment. Unsurprisingly, most of these trials are for lung and breast cancers: 71/206 trials of HER1/2 inhibitors and 16/71 of IGF-1R inhibitors are for treating lung cancers; and 44/206 trials of HER 1/2 inhibitors and 9/71 trials are for treating breast cancers. Their effects in combination of chemotherapeutics have been generally studied. A phase II trial (NCT00986674) demonstrated that carboplatin and paclitaxel are more effective when given with cixutumumab (anti-EGFR antibody) and cetuximab (anti-IGF-1R antibody) than with cetuximab alone in treating advanced non-small cell lung cancer, with overall response rates of 22%, 21.7% and 11%, respectively. However, a phase II trial (NCT00684983) showed that cixutumumab did not enhance the effects of capecitabine and lapatinib ditosylate (EGFR and HER2 inhibitors) in treating HER2-positive stage IIIB-IV breast cancers. Five trials with published results showed limited effects of FGFR inhibitors. A phase II trial studied the effects of dovitinib (a multitargeted inhibitor of FGFR and VEGFR) for patients with advanced lung cancer or CRC who have progressed on anti-VEGF treatment, and the overall response rate was 14.3%. Overall, blockade of growth factor receptors brings considerable therapeutic effects when combining with chemotherapy in treating certain cancers.

IL-4 and IL-13 function as immunosuppressive cytokines that inhibit antitumor immunity by enhancing the Th2 cell response and blocking Th1 cell differentiation.16 Mutated forms of IL-4 and IL-13 receptors highly expressed in multiple human tumor cell lines.49,50 Based on these observations, targeted drugs were developed by linking Pseudomonas exotoxin to IL-4 or IL-13 (IL4-PE38KDEL and IL13-PE38QQR, respectively).

Since 2001, there have been 7 cancer trials of IL-4 registered at ClinicalTrial.gov. It was shown in vitro that IL-4 can inhibit the growth of Kaposi sarcoma cells,51 and one trial assessed the efficacy of IL-4 in the treatment of 48 patients with Kaposi sarcoma (NCT00000769) although no findings have been published. IL-4 was also administered as an adjuvant to enhance the effect of a DC vaccine in the treatment of Wilms tumor (NCT00001564) and Ewing sarcoma (NCT00923910),52 but the outcome of these trials is unknown.

The first clinical trial using IL13-PE38QQR (for the treatment of malignant gliomas) was initiated in 2000. Since then, there have been 10 clinical trials involving over 500 participants with malignant gliomas who were treated with IL-13-PE38QQR. It is difficult to conclude these trials as the results have not been published. In one phase III trial of 300 patients with recurrent malignant gliomas (NCT00064779), IL13-PE38QQR was directly infused into the tumor tissue for 96 hours. After 15 days, patients underwent surgery to excise the recurrent tumors and received another infusion. However, no results have been posted for this or any other trial investigating IL13-PE38QQR.

IL-10 functions as an immune suppressor that inhibits the cancer immunity cycle.53 To date, there have been no reports from ClinicalTrial.gov evaluating the efficacy of IL-10 for cancer treatment, although many trials have examined the use of IL-10 for the treatment of autoimmune disease such as rheumatic arthritis.

The IL-6 cytokine family, which includes IL-6 and IL-11, participates in the activation of oncogenic signal transducer and activator of transcription (STAT)3.54 Twenty trials of IL-6 for cancer treatment (multiple myeloma, lymphoma, mRCC, and prostate cancer) have been registered at ClinicalTrials.gov, mostly involving siltuximab, an IL-6 antagonist approved by the FDA for the treatment of multicentric Castleman disease. In a phase II trial of 88 patients with myeloma (NCT00911859), siltuximab combined with VELCADE (a prescription medication for myeloma) resulted in a higher complete response rate (26.5% vs 22.4%) and overall response rate (87.8% vs 79.6%) than VELCADE alone; in the second part of this trial (286 patients; NCT00401843), PFS of the 2 groups was 245 and 232 days, respectively. Given its role in hematopoiesis, IL-11 has been investigated for its potential to increase platelet counts in patients with chronic myelogenous leukemia in 2 trials.

IL-17 is a pro-oncogenic cytokine that is mainly produced by Th17 cells and induces the production of IL-6 by tumor cells to activate the IL-6/STAT3 signaling pathway.55 Elevated IL-17 expression is related to poor prognosis in patients with invasive ductal carcinoma. But no cancer clinical trial using or targeting IL-17 has been published in ClinicalTrial.gov.

According to review of hundreds of clinical trials, we know that efficacy of cytokines as therapeutic drugs on clinical outcomes are limited. One possible reason for this is that because of the short half-life of cytokines in the blood, frequent high doses are required to achieve lasting therapeutic effects. For example, the effective dosage of IL-2 is 600,000 IU/kg administered every 8 hours for 5 days; moreover, 3 treatment cycles are needed for its activity. Because of this, adverse events generally occur in patients receiving cytokine therapy, include fatigue, chills, fever, chest pain, and musculoskeletal pain.56 More serious adverse events are gastrointestinal disorders (eg, stomachache, diarrhea, and gastritis), cardiac abnormalities (eg, myocardial infarction, nodal tachycardia), and disorders of the immune system (eg, anaphylaxis) and blood and lymphatic systems (eg, anemia and febrile neutropenia).

Nanomaterials used as carriers to deliver cytokines to target tissues can improve the stability of cytokines in blood and reduce their toxicity. At the same time, the unique features of nanomaterials have advantages for the therapeutic application of cytokines including aqueous solubility, prolonged circulation time, and preferential accumulation at tumor sites.57 Recent studies on nanomaterials used for cytokine loading are summarized in Table 2.

Table 2 Nanomaterials for Therapeutic Delivery of Cytokines

Nanomaterials can improve the stability and bioactivity of cytokines. For example, sustained released over a period of 1 month was achieved for IFN- encapsulated in poloxamer-blend microspheres.58 Chitosan coated with pJME/GM-CSF (plasmid DNA) was more effective than naked pJME/GM-CSF in promoting DC recruitment.59 Nanoscale liposomal polymeric gels loaded with TGF- inhibitor and IL-2 delayed tumor growth and increased NK cell activity and the number of tumor-infiltrating T cells.60 Nanomaterials can also reduce the toxic effects of cytokine therapy; for instance, encapsulation in PEG liposomes abrogated the diarrhea induced by TNF in rats with subcutaneous BN175 sarcomas.61 Gold nanoparticles were found to enhance the accumulation of TNF around blood vessels in a mouse model of epithelial carcinoma, leading to a significant decrease in tumor volume.62 Magnetic nanoparticles carrying human IFN-2b were enriched in the liver upon application of a magnetic field and compared to the control group, the volume of human liver cancer cell-derived tumors in nude mice was reduced by about 30%.63 Nanomaterials are good auxiliaries for cytokine gene therapy. Chitosan coated with plasmids encoding the cytokines IL-15 and IL-21 suppressed tumor growth and prolonged survival in mice.64,65 PEGpoly (lactic-co-glycolic acid)PEG nanoparticles were shown to be effective carriers for IL18 gene delivery.66 Magnetic nanoparticles carrying a plasmid encoding a small interfering RNA targeting gene encoding epidermal growth factor receptor reduced endogenous epidermal growth factor receptor expression in U251 glioma cells, resulting in tumor regression in vivo.67 Two clinical trials involving 168 patients have investigated the efficacy of colloidal gold-bound TNF for the treatment of primary or metastatic cancer (NCT00356980 and NCT00436410, respectively), but the results have yet to be reported.

Besides, artificial oncolytic viruses are well-established carriers for cytokine gene therapy. There are 17 cytokines including CCL2, CCL5, CCL19, CXCL11, FGF2, FLT3L, GM-CSF, IFN-/, IFN-, IL-2, IL-7, IL-12, IL-15, IL-18, IL-23, IL-24, and TNF- that are delivered by artificial oncolytic viruses derived from adenovirus, herpesvirus, paramyxovirus, poxvirus, or rhabdovirus. More details could be found in the recent review wrote by Pol et al.68

Although animal studies showed that properties and efficacy of cytokine-based drugs can be improved by nanomaterials, sufficient clinical studies are required to support the conclusion. Two ongoing clinical trials involving 168 patients aim to investigate the efficacy of colloidal gold-bound TNF for the treatment of primary or metastatic cancer (NCT00356980 and NCT00436410, respectively), but the results have yet to be reported.

As important immune regulators, cytokine-based drugs offer many possibilities for cancer treatment. Large amounts of cytokines can be readily produced using eukaryotic or prokaryotic expression systems as the cDNA sequences of most cytokines are available, which makes cytokines attractive to new drug development. However, our statistical results (Supplementary Table 1) indicate that a large number of clinical trials of cytokine-based drugs ended up without published results mainly because of the low efficacy, serious adverse effects, and antagonistic roles in immunoregulation. These problems are partly overcome by delivering with nanomaterials or oncolytic viruses in animal experiments, or combining with immunotherapies or chemotherapeutic agents or both (Figure 6B and C) in clinic. Such strategies would be used and improved in the future clinical trials. Moreover, clarifying the immune-regulatory mechanisms of cytokines can improve their efficacy and safety in cancer therapy.

APC, antigen-presenting cell; B7-H3, B7 homolog 3 protein; CAR-T, chimeric antigen receptor T cell; CCL, C-C motif chemokine ligand; CRC, colorectal cancer; CSF, colony-stimulating factor; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T lymphocyte-associated protein 4; CXCL, chemokine (C-X-C motif) ligand; DC, dendritic cell; EGF, epidermal growth factor; EMT, epithelial-to-mesenchymal transition; EPO, erythropoietin; FDA, US Food and Drug Administration; FGF, broblast growth factor; Fu, fluorouracil; G, granulocyte; GM, granulocyte/macrophage; IFN, interferon; IGF, insulin-like growth factor; IL, interleukin; ILC, innate lymphoid cell; i.v., intravenous injection; IU, international unit; JAK, Janus kinase; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; mRCC, metastatic renal cell carcinoma; NK, natural killer; NKT, natural killer T; NSCLC, non-small-cell-lung cancer; ORR, objective response rate; OS, overall survival; PD-1, programmed death 1; PD-L1, programmed death ligand 1; PEG, pegylated; PFS, progression-free survival; PGE2, prostaglandin E2; PLGA, poly (lactic-co-glycolic acid); rAd, recombinant adenovirus; STAT, signal transducer and activator of transcription; s.c., subcutaneous injection. TAA, tumor-associated antigen; TAM, tumor-associated macrophage; TGF-, transforming growth factor ; Th, T helper cell; TNF, tumor necrosis factor; Treg, regulatory T cell; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

This work is supported by the National Natural Science Foundation of China (Grant No. 31800006) to YQ; Natural Science Foundation of Guangdong Province (Grant No. 18zxxt26) to YQ; Guangzhou Basic and Applied Basic Research Foundation (Grant No. 202002030127) to JS; Guangdong Basic and Applied Basic Research Foundation (Grant No. 2021A1515012324) to JS; the Fundamental Research Funds for the Central Universities (Grant No. 20ykzd08) to JS; Natural Science Foundation of Guangdong Province (Grant No. 2018A030313563) to JS; Program for Guangdong Introducing Innovative and Entrepreneurial Teams (Grant No. 2016ZT06S252) to JS; Guangdong Financial Fund for High-Caliber Hospital Construction to JS.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

The authors declare they have no competing financial interests and other onflicts of interest in this work.

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Clinical Application of Cytokines in Cancer Immunotherapy | DDDT - Dove Medical Press

Cardiac Stem Cells Comments Off on Clinical Application of Cytokines in Cancer Immunotherapy | DDDT – Dove Medical Press | May 28th, 2021

World Blood Cancer Day is marked today. The celebration of this day was instituted in 2014 because, in 1991, Methchild Ehringer could not find a match by a German non-profit organisation DKMS founded by Methchilds family. She died because she was unable to find a match. The aim was and still remains to find a potential donor for every person needy of a bone marrow/stem cell transplant.

Today, there are 10 million potential donors registered when compared to the initial 3,000. Some might remember me as the person who needs Daratumumab included in the government formulary for free medicinals. I am interested in other matters too!

World Blood Cancer Day! This day highlights a more personal issue that concerns the realisation that I do not stand alone in my blood cancer journey. An issue that cuts across the three most common blood cancers: leukaemia, lymphoma and myeloma. Of these three, the lymphomas and the myelomas are the more common. For many people, such as myself, the diagnosis of a blood cancer is a shock. Like water, blood is meant to sustain a person.

Blood cancers bring along with them a lot of uncertainty and anxiety. For some blood cancers, such as multiple myeloma, a cure does not exist. To suddenly acknowledge that what is being generated in your bone marrow and what is circulating around your body and through your own blood is threatening you and your body, is psychologically invasive in a way like no other. I felt robbed. Robbed by my own body, my own immune system and, perhaps, by my own past lifestyle choices.

Stem cell transplantation offers hope of increased longevity, when appropriate, to a good proportion of blood cancer patients. A successful stem cell transplant means time out of hospital, visiting usually only every few months for monitoring. There are two types of stem cell transplantation: autologous and allogenic.

Autologous transplantation is when a person donates to oneself. As was the case with myself and my two attempts for autologous transplantation.

For many people, such as myself, the diagnosis of a blood cancer is a shock

Allogenic requires matching a donor to a patient. This is only suitable in specific cases. The government of Malta does pay for such transplantation. Charities such as Puttinu are incredibly supportive in supporting those undergoing stem cell transplantation by providing accommodation. On World Blood Cancer Day 2021, my wish is that the Maltese public understand what I consider to be three critical issues.

First, for many, stem cell/bone marrow transplants and, increasingly, cellular innovative therapies, potentially require a donor. Second, for a portion of those requiring such intervention/therapy they cannot donate to themselves and/or find a donor from their family. Third, millions of people are required to donate their stem cells.

As of today, I am under the impression that Malta and its generally very good healthcare system does not yet, have a register for stem cell donation. I hope I am wrong. Should I be right, I urge the powers that be to strongly consider this as part of their long-term strategic vision. What I do know, however, is that Malta has the local expertise and the equipment to collect stem cell transplants.

Perhaps because it is a small-island state, Malta does not have the facility for storage. The healthcare system is probably likely, especially at this point in time, not to possess as much capacity to assure consistent and sustained storage of stem cells according to European and international gold-standard criterion. This is likely to be primarily due to space issues given that the local expertise is available and excellent.

In more recent times especially, monoclonal agents, such as Daratumumab, are increasingly offered as more frontline treatment to those with an early diagnosis of multiple myeloma, at least in other EU countries and to those able to afford payment.

Chimeric Antigen therapy (CAR-T cell), which forms part of cellular therapeutic options, is also in the pipeline.

Monoclonal therapy and CAR-T cell are consequently likely to decrease the need for stem cell transplants. This is positive but, if anything, highlights even more the need for a stem cell database, register and repository. Newer therapies generally tend to be increasingly stem cell therapy dependent in some form or other.

What I would like the reader to appreciate is that I am not a medical professional. I have been at times accused of being a dreamer but life has taught me two things.

To turn lemons into lemonade and to give without the expectation of taking or receiving.

Today, I would like to go a bit beyond my myeloma, so to speak. I want to celebrate, as a blood cancer survivor, what works for me. I urge all of you to read about blood cancers and try to empathise with all blood cancer survivors.

Above all, let us not forget their carers: spouses, children, friends, doctors, nurses and everybody else whom I have inadvertently omitted.

I, for one, would not be here, especially, without the excellent care and patience of doctors, nurses, physiotherapists, etc. alongside the emotional care, motivation and interest offered by my sons, friends, work colleagues and those generally understanding and supportive of my condition, and, yes, my Lara still needs Dara quest! Thank you.

Lara Saids dream is to set up a non-profit organisation to advocate especially for the rights of patients with myeloma, leukaemia and lymphoma for Malta and Gozo. She is here appealing to survivors, their relatives and/or carers to help her set up a patient group.

Lara Said, Multiple myeloma survivor, member, Myeloma Patients Europe

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Living with blood cancer - Lara Said - Times of Malta

Bone Marrow Stem Cells Comments Off on Living with blood cancer – Lara Said – Times of Malta | May 28th, 2021

Ifeyinwa Osunkwo, MD, MPH: Pat, can you describe the steps people go through to do a bone marrow transplant to gene therapy? Set the stage to help people understand why busulfan and why were talking about mutations. Can you walk us through the whole gene therapy process?

Patrick McGann, MD, MS: With transplant or gene therapy, the term transplant could be autologous, meaning your own cell gene therapy transplant. Its not as if youre transplanting a solid organ or a kidney. Sometimes patients get confused about this. Its looks like a blood transfusion hanging when it eventually goes in. For a bone marrow transplant, the donorwhoever that iseither gets a bone marrow aspiration, where they get bone marrow cells taken from their bone marrow, or a medicine to rev up their blood cells and get blood taken just from their vein. The patient needs to get prepared because they need to get rid of all their sickle cells. They need to suppress their immune system, so they dont reject this foreign cell, which is someone elses.

We use strong chemotherapy. If you have leukemia, as a comparison, you need to kill every last leukemia cell, and you get blasted with really strong chemotherapy agents and strong immunosuppressive agents. This is usually a week or so before; the days are counted backward. The cells that go in your body are most vulnerable to infection to everything. Its a dangerous time. Thats when complications come in. If its a transplant, you get infused with that donors bone marrow cells and hope it takes. It takes some weeks time for your body to take those new cells, and youre often receiving antibiotics and getting transfused and sustaining it, because your bone marrow is still not working. Basically, your immune system is suppressed. Its a tough time.

Transplant conditioning, as this regimen is called, has gotten a little less toxicreduced conditioning is the term. But thats still serious conditioning. Even though its reduced from what it used to be, its a relative term. Gene therapy is a little different because youre giving back your own cell. The way gene therapy happens is its ex vivo, meaning they take it out of your body. There are different ways that this is being done. Many patients need to have a bone marrow aspiration or many procedures to take enough cells out of their bone marrow to take them to the lab to fix them. There have been new ways to do this with peripheral blood and a medication called plerixafor, which is much better than going to the operating room for these horrible procedures.

Those cells are then taken to the lab and edited, or whatever the mechanism of gene therapy is. You still need to ablate your bone marrow to get rid of all your sickle cells. Because if you have any or many sickle cells in there, when you give back your edited gene cells, those will just take over. You still need to suppress that bone marrow. Because its your own cells, the immune suppression isnt as much of a problem as it is with transplant. Still, its a week of pretty serious medicinebusulfan, traditionallyand youre in the hospital for less of a period of time than transplant. Its quite an ordeal. Similarly, it takes or doesnt, and you monitor over time if that gene therapy has worked and whether its sustainablecross your fingersin the long term.

Ifeyinwa Osunkwo, MD, MPH: Basically, you have 2 options. The first option, you have to kill off their own bone marrow cells using chemotherapy. Then you give them somebody elses bone marrow, like a blood transfusion. The stem cells from the other person finds its way into their bone marrow and then grows. Then you wait and see what happens. Do you fight it? Do you accept it? We know if it takes or not. For gene therapy, we take out the patient stem cells, take it to a laboratory. Its usually in New Jerseydont ask me why. They manipulate it to pick out the gene they dont want. Then they give that patient back their own modified stem cells and wait for it to grow. But you still have to wipe out that persons bone marrow, so you dont have this fight going on. Even though theyre your cells, theyre a little different with the new gene change that has been made. Its a complicated process, and its really the only way to cure your disease. Either stem cell or gene therapy. We have had some setbacks in the past and more recently, but I believe that science is going to prevail. Over time were going to get to the point where we figure out the way to do this in the safest way to make it available to the most people with sickle cell disease and other blood disorders.

Thank you so much for watching this HCPLive Peer Exchange. If you enjoyed the content, please subscribe to the e-newsletter to receive upcoming Peer Exchanges and other great content right in your in-box.

Transcript Edited for Clarity

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Stem Cell vs Gene Therapy Processes in SCD - MD Magazine

Bone Marrow Stem Cells Comments Off on Stem Cell vs Gene Therapy Processes in SCD – MD Magazine | May 28th, 2021

Fighter: A year long battle but Rory is still smiling

In January 10-year-old Aurora Pile-Grays family were told they may lose their little girl as a rare and aggressive cancer took its devastating toll.

The previous November Aurora affectionately known as Rory had been declared in remission from the disease that she had been fighting since May 2020 but a cruel blow saw a severe relapse with the cancer progressing to her skull, eyes, neck, spine, liver, kidneys, lungs, abdomen and pelvis.

A discussion with the consultant over going home from hospital and preparing for end of life care took place but lion-hearted Rory was not ready to give up her fight against Burkitts Lymphoma which affects blood and bone marrow and her family were not ready to let go.

After a year-long battle with the disease, seven rounds of intensive chemotherapy, stays in Royal Marsden and Great Ormond Street hospitals and targeted therapy with trial drug Inotuzumab, Aurora was declared cancer free again at the end of April.

The Inotuzumab drug also offered the family, who live in Garlinge, a chance for Aurora to be at home despite treatment.

Mum Keisha, 28, said: We chose Inotuzumab because it meant a better quality of life for Rory, she could come home to us and her brother and sister rather than having to be in hospital.

The trial drug, and cancer all clear, opened the way for the youngster to undergo a bone marrow transplant on May 13 all the more vital as chemo had wiped out her immune system.

First there were 10 radiotherapy sessions to get through involving cranial boost, where Auroras face was bolted to the bed so she couldnt move.

The transplant which is universally referred to as a new birthday to signal a second chance at life took place at the Marsden and involved replacing old bone marrow cells that are failing to produce healthy new cells, with cells from a donor. The aim is to create a new immune system and hopefully prevent cancer returning or mutations occurring.

The stem cells Aurora now carries should begin to reproduce in her own body and allow her bone marrow to work as normal in producing healthy red cells, white cells and platelets, since her body is no longer capable of doing so after the effects of both the cancer and the treatment.

Auroras donor cells were frozen in December which meant on the day they had to be defrosted and infused within 20 minutes. Auroras donor produced nine bags of stem cells. Only four were required, leaving 5 for future use if needed.

Each bag is defrosted in a water bath around 38 degrees so that by the time its infused its not too different to body temperature. They are then put into separate syringes and pushed through a central line into the body.

The family have been told there is just a 10-20% chance that the transplant will achieve long lasting remission, but the St Crispins school youngster has so far beaten the odds and mum Keisha says her little girl is a fighter.

In her blog Growing Pains and Paper Planes, Keisha says: Shes been amazing throughout this entire journey and Im unbelievably proud to call her my daughter. Im in awe of her strength, determination and resilience and shes shown us all that sometimes the smallest hearts overcome the biggest battles.

So far Aurora has responded well to the transplant and there is evidence of engraftment where the donor cells find their way to her bone marrow and begin to make new blood cells. White cells are the first to engraft which include neutrophils, then red cells and then platelets.

Keisha said: We were worried the effects would be awful as Rory was so sensitive to the chemo but it is going really well.

Rory is up every day, listening to audio books and doing lots of colouring, cracking jokes and just being Rory.

It is such a relief. In January when we realised the cancer had spread and she could lose the use of her legs, bladder and bowel we had to talk about making her comfortable at home. But we were not ready to give up. I said it wasnt that time yet, not all the time that Rory was laughing and joking and looking forward to seeing her brother and sister. She wasnt giving up and we werent.

Now there has been this complete 360 turnaround. Everything still depends on how she takes to the transplant. On day 28 a sample will hopefully show what percentage are donor (cells) and what percentage are her own. Hopefully it will show primarily donor.

Rory is on immunosuppressants for up to a year but potentially could be able to return to school in six months time.

Keisha said: Shell go back as a Year 6 and has missed two years but has been doing schoolwork for an hour each day.

She is looking forward to it, more the social side than the work!

Rory has won the hearts of the Thanet community during her battle with cancer with many following the familys progress through Keishas blog and also donating to a fundraiser for life-saving treatment. People also signed up on the bone marrow register following Keishas highlighting of the desperate need for donors, especially people of mixed ethnicity.

Keisha said: We are unbelievably grateful and humbled by the support people have shown us over the past year. The kind words, the gestures, the gifts, the donations, the shares, the marrow registrations and the sense of community has helped us more than you will ever know.

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'Lion-hearted' ten-year-old Aurora's 'second chance' at life after cancer remission and stem cell transplant - The Isle of Thanet News

Bone Marrow Stem Cells Comments Off on ‘Lion-hearted’ ten-year-old Aurora’s ‘second chance’ at life after cancer remission and stem cell transplant – The Isle of Thanet News | May 28th, 2021

Magenta Therapeutics is losing its chief medical officer and head of R&D John Davis, M.D., with his last day coming July 30.

Davis helped steer the biotechs early path as well as deals with Avrobio and base editing biotech Beam Therapeutics around its lead stem cell conditioning program, MGTA-117, and MGTA-145 as a potentially new first-line standard of care for stem cell mobilization in a broad range of diseases. His departure comes three years after he joined the company from Pfizer, where he led its early R&D.

The biotech was keen to stress in an 8-K SEC filing (but not a press release) that his departure was not related to any disagreements with the Company on any matter relating to its operations, policies, practices or any issues regarding financial disclosures, accounting or legal matters.

It will now look for a new CMO, while Davis will become an adviser to the company.

RELATED: Magenta CSO Cooke jumps to IFM Therapeutics

This isnt the first move within the R&D ranks: Magenta started 2020 by losing its chief scientific officer when Michael Cooke, Ph.D., hopped over to IFM Therapeutics. In the fall, though, it nabbed Lisa Olson, Ph.D., who previously led immunology discovery at AbbVie, as his replacement.

Conditioning is a necessary step for some gene therapies, but one that can cause side effects like nausea, hair loss and mouth sores or make patients more vulnerable to infection. Magentas platform is based on looking to improve on current methods with an antibody-drug conjugate.

MGTA0117 is made up of an anti-CD117 antibody linked to amanitin, a cell-killing toxin. It is designed to target only hematopoietic, or blood-forming, stem cells and progenitor cells.

Animal studies suggest it could clear space in bone marrow for gene-modified stem cells to take root, Magenta said. The company plans to wrap IND-enabling studies for the antibody-drug conjugate this summer.

MGTA-145, meanwhile, just finished off a midstage test earlier this month, hitting its primary endpoint in a small multiple myeloma study.

Davis' replacement will already have a lot of clinical work on their hands.

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Magenta Therapeutics' research lead Davis hits the exit for family reasons - FierceBiotech

Bone Marrow Stem Cells Comments Off on Magenta Therapeutics’ research lead Davis hits the exit for family reasons – FierceBiotech | May 28th, 2021

Chronic lymphocytic leukemia (CLL) is a type of blood cancer. It affects lymphocytes, a type of immature white blood cell that the body produces in the bone marrow.

People with CLL may experience discomfort, swelling, and pain in the abdomen if their spleen enlarges. In rare cases, CLL can also affect mucosal tissues, such as those lining the gastrointestinal (GI) tract.

This article discusses the link between CLL and stomach pain in more detail. It also looks at ways to prevent and treat CLL, the other possible symptoms, and the outlook for people with this condition.

People with CLL may experience various symptoms involving the abdomen or stomach, such as:

In most cases, people with CLL do not experience abdominal symptoms due to the disease until it progresses and becomes more severe.

Research suggests that CLL infiltrates and affects the GI tract in about 5.713% of cases. When CLL affects the GI tract, doctors may call it Richters syndrome.

People with CLL may experience abdominal swelling, discomfort, and tenderness as a result of their spleen becoming larger. Less commonly, they may also feel full after eating small amounts of food, as the spleen can press on the stomach, making it smaller and able to hold less.

In rare cases, CLL infiltrates the lining of the GI tract, causing inflammation and ulcers or open wounds. People may experience symptoms similar to those of inflammatory bowel disease (IBD) and malabsorption disorders. These symptoms may include diarrhea, nausea, vomiting, abdominal pain and cramping, and unintentional weight loss.

CLL is cancer that develops in lymphocytes, which are white blood cells that form in the bone marrow and help fight infection.

Lymphocytes make up most of the lymph tissues in the lymph nodes, thymus gland, adenoids, tonsils, and spleen. They are also present in the GI tract, bone marrow, and respiratory system.

CLL is a type of leukemia that develops gradually over time.

About 5075% of people with CLL do not experience noticeable symptoms. Due to this, doctors diagnose most people with CLL during routine blood work.

The symptoms of CLL often begin when the cancerous cells crowd out healthy cells in the bone marrow or migrate to other organs or tissues. When symptoms first appear, they are typically mild, but they then become increasingly severe. CLL can cause many nonspecific symptoms, so a person may feel as though they have a cold or the flu.

Possible symptoms of CLL that do not relate to the abdominal area include:

Doctors do not yet have a way to prevent leukemia. However, some types of leukemia, including CLL, may have links to toxins, such as herbicides, pesticides, radon, and tobacco exposure. People can help reduce the risk of CLL by avoiding or practicing extreme caution around these toxins.

Many people do not experience symptoms of CLL for years and do not require treatment. However, as the disease progresses, these individuals may need treatment to extend their lives.

When and how a doctor treats someones CLL depends on a few factors, including:

Chemotherapy is typically the first-line therapy for CLL.

Doctors may use chemotherapy in conjunction with other treatment options, such as monoclonal antibody therapy. This therapy binds antibodies to cancer cells and destroys them. Treatment can also include medications to treat or prevent infections or improve low blood cell levels.

For instance, some people may take a combination of the monoclonal antibody rituximab and the chemotherapy drugs fludarabine and cyclophosphamide. Alongside the oral chemotherapy medication chlorambucil, doctors use obinutuzumab or ofatumumab, which have the same drug target as rituximab.

Small molecule inhibitors, such as bendamustine hydrochloride, idelalisib, and ibrutinib, can also sometimes form part of a CLL treatment regimen.

In 2017, the Food and Drug Administration (FDA) approved the combination medication Rituxan Hyecela (rituximab and hyaluronidase human) for CLL treatment.

In recurring or aggressive cases of CLL, an individual may have a blood or bone marrow stem cell transplant. This procedure replaces diseased cells with healthy blood cells that are able to mature into bone marrow cells.

Doctors may treat CLL until the symptoms lessen and then stop treatment until the symptoms worsen again.

Many people with CLL live for many years with a high quality of life.

There is no cure for CLL, so treatment aims to extend and improve someones life by reducing their symptoms. Doctors treat many people intermittently as their symptoms reoccur.

A persons outlook depends on their age, overall health, underlying conditions, and stage of CLL. Typically, people who are over the age of 65 years or have a more advanced stage of CLL have a less positive outlook.

Genetic changes in CLL cells and increased beta-2 microglobulin protein levels in the blood can make CLL more challenging to treat, potentially affecting a persons outlook.

Doctors classify people with CLL into different risk groups depending on certain factors. Based on these risk groups, the estimated percentages of people surviving 5 years or more after their diagnosis is:

People with more advanced or severe CLL may experience abdominal swelling, discomfort, tenderness, and pain. They may also feel full after eating small amounts. More rarely, someone with CLL may develop GI tract inflammation or ulcers, which can cause symptoms such as diarrhea, nausea, vomiting, cramping, and unexplained weight loss.

Anyone who thinks that they may have CLL should speak with a doctor. People with a confirmed diagnosis who experience symptoms of more advanced or severe CLL, such as abdominal pain, should also seek medical care.

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Chronic lymphocytic leukemia and stomach pain: What is the link? - Medical News Today

Bone Marrow Stem Cells Comments Off on Chronic lymphocytic leukemia and stomach pain: What is the link? – Medical News Today | May 28th, 2021

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Moderna, Inc., (Nasdaq: MRNA) a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, today announced new research being highlighted as part of the Companys fourth annual Science Day. Modernas Science Day is designed to provide insight into the continued diverse efforts underway at Moderna to better understand how to use mRNA as medicines and vaccines and underscores the Companys continued commitment to basic science and innovation.

Science Day gives us an opportunity to provide insights into the advancements in our platform science and our further understanding of how to use mRNA as both a vaccine and a medicine. Our investments in basic science continue to result in major steps forward in our platforms capabilities, and these have allowed us to open new therapeutic areas and new scientific directions, said Stephen Hoge, M.D., President of Moderna. Our investments in platform research along with our digital backbone and manufacturing plants have enabled us to create first-in-class mRNA medicines and vaccines. Today, we're excited to highlight our work to identify and address SARS-CoV-2 variants of concern, optimize our proprietary lipid nanoparticle (LNP) technology, and deliver mRNA to hematopoietic stem cells.

Moderna currently has 24 mRNA development programs in its portfolio with 14 having entered clinical studies. The Companys updated pipeline can be found at http://www.modernatx.com/pipeline. Moderna and collaborators have published more than 65 peer-reviewed papers.

At this years Science Day, Moderna will present new platform science and preclinical research, including:

mRNA Delivery to Hematopoietic Stem and Progenitor Cells (HSPC)

Of the nearly 30 trillion cells in the body, approximately 90% are of hematopoietic origin. Hematopoietic lineages originating in the bone marrow are intimately involved in maintaining homeostasis and human health. Nonetheless, there are hundreds of hematologic or immune-related disorders caused or exacerbated by cells of the hematopoietic lineage. In a disease setting, cells of hematopoietic origin interact with host tissues to drive chronic inflammatory and immune disorders. Because some hematopoietic stem and progenitor cells (HSPC) have self-renewal and pluripotent properties, targeting HSPC has the potential to modulate underlying chronic inflammation and immune-related disorders.

Advances in lipid nanoparticle (LNP) technology has allowed for delivery to the bone marrow following systemic LNP administration in vivo. This achievement has enabled Moderna scientists to deliver mRNA directly to bone marrow HSPC in vivo, leading to HSPC transfection and long-term modulation of all hematopoietic lineages. This represents a major milestone in impacting chronic inflammatory and immune related disease.

mRNA Engineering: Optimizing Ribosome Load

The ribosome plays a central role in orchestrating the life of mRNA inside the cell. Understanding how to modulate translation by changing mRNA sequence could enable a powerful lever to control the performance of an mRNA drug. To develop such a lever, the Moderna's scientists strove to characterize mechanistically how differences in translation drive differences in protein expression. In this research, an unexpected relationship emerged where mRNAs with low translation initiation rates conferred the highest and most durable levels of protein expression. By understanding the mechanisms that drive this behavior, the Company is taking mRNA design from a guess-and-check discipline into an engineering discipline. With tools in place, and more under development, Moderna is improving its ability to make an mRNA that generates the right amount of the right protein, for the right amount of time, in the right cell type. As Moderna builds these levers into its mRNA drugs, the Company believes it will be able to target more indications with more precision.

Addressing SARS-CoV-2 Variants of Concern

One part of the Companys strategy to remain ahead of the SARS-CoV-2 virus is to closely monitor and address emerging variants of concern and waning immunity. Moderna is using artificial intelligence (AI) and machine learning to predict escape risk. This involves developing statistical models to understand and predict escape risk, including identifying breakthrough sequences from clinical trials and real-world data, examining spike protein biophysical and pseudovirus neutralization data, studying spike mutations and lineage info, and time tracking.

Science Day Webcast Information

Moderna will host its annual Science Day for analysts and investors at 8:00 a.m. ET on Thursday, May 27. A live webcast will be available under Events and Presentations in the Investors section of the Moderna website at investors.modernatx.com. A replay of the webcast will be archived on Modernas website for one year following the presentation.

About Moderna

In 10 years since its inception, Moderna has transformed from a science research-stage company advancing programs in the field of messenger RNA (mRNA), to an enterprise with a diverse clinical portfolio of vaccines and therapeutics across six modalities, a broad intellectual property portfolio in areas including mRNA and lipid nanoparticle formulation, and an integrated manufacturing plant that allows for both clinical and commercial production at scale and at unprecedented speed. Moderna maintains alliances with a broad range of domestic and overseas government and commercial collaborators, which has allowed for the pursuit of both groundbreaking science and rapid scaling of manufacturing. Most recently, Modernas capabilities have come together to allow the authorized use of one of the earliest and most-effective vaccines against the COVID-19 pandemic.

Modernas mRNA platform builds on continuous advances in basic and applied mRNA science, delivery technology and manufacturing, and has allowed the development of therapeutics and vaccines for infectious diseases, immuno-oncology, rare diseases, cardiovascular diseases and auto-immune diseases. Today, 24 development programs are underway across these therapeutic areas, with 14 programs having entered the clinic. Moderna has been named a top biopharmaceutical employer by Science for the past six years. To learn more, visit http://www.modernatx.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements regarding: the potential for delivery of mRNA to hematopoietic stem and progenitor cells (HSPC) in vivo; methods of detecting and interrogating HSPC in vivo; the potential for delivering LNPs to hematopoietic stem cells in vivo; the ability to optimize codons and mRNA structures to increase total protein outputs; the potential for the Company to develop processes for controlling protein expression by modifying ribosomal loads; the Companys ability to engineer LNPs capable of accessing difficult-to-transfect primary cells with efficient endosomal escape and high functional mRNA delivery; the Companys strategy for combatting COVID-19, including processes for monitoring emerging variants and waning immunity; and strategies for modeling viral escape. In some cases, forward-looking statements can be identified by terminology such as will, may, should, could, expects, intends, plans, aims, anticipates, believes, estimates, predicts, potential, continue, or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond Modernas control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties, and other factors include, among others: the fact that there has never been a commercial product utilizing mRNA technology approved for use; the fact that the rapid response technology in use by Moderna is still being developed and implemented; the safety, tolerability and efficacy profile of the Moderna COVID-19 Vaccine observed to date may change adversely in ongoing analyses of trial data or subsequent to commercialization; the Moderna COVID-19 Vaccine may prove less effective against variants of the SARS-CoV-2 virus, or the Company may be unsuccessful in developing future versions of its vaccine against these variants; despite having ongoing interactions with the FDA or other regulatory agencies, the FDA or such other regulatory agencies may not agree with the Companys regulatory approval strategies, components of our filings, such as clinical trial designs, conduct and methodologies, or the sufficiency of data submitted; Moderna may encounter delays in meeting manufacturing or supply timelines or disruptions in its distribution plans for the Moderna COVID-19 Vaccine; whether and when any biologics license applications and/or additional emergency use authorization applications may be filed in various jurisdictions and ultimately approved by regulatory authorities; potential adverse impacts due to the global COVID-19 pandemic such as delays in regulatory review, manufacturing and clinical trials, supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; and those other risks and uncertainties described under the heading Risk Factors in Modernas most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent filings made by Moderna with the SEC, which are available on the SECs website at http://www.sec.gov. Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. These forward-looking statements are based on Modernas current expectations and speak only as of the date hereof.

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Moderna Highlights Advances in Platform Science and Innovative Vaccine Research at Fourth Annual Science Day - Business Wire

Bone Marrow Stem Cells Comments Off on Moderna Highlights Advances in Platform Science and Innovative Vaccine Research at Fourth Annual Science Day – Business Wire | May 28th, 2021

REDWOOD CITY, Calif.--(BUSINESS WIRE)--Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, today announced the initiation of a Phase 1/2 clinical trial to evaluate JSP191, the companys first-in-class anti-CD117 monoclonal antibody, as a targeted, non-toxic conditioning regimen prior to allogeneic transplant for chronic granulomatous disease (CGD). Jasper Therapeutics and the National Institute of Allergy and Infectious Diseases (NIAID) have entered into a clinical trial agreement in which NIAID will serve as the Investigational New Drug (IND) sponsor for this study.

CGD is a rare, inherited disease of the immune system that develops in infancy or early childhood and results in severe and sometimes life-threatening infections. Allogeneic hematopoietic stem cell transplant is a proven cure for CGD. However, its use is limited because current conditioning agents used to deplete stem cells in preparation for transplantation are genotoxic and associated with limited efficacy and serious adverse effects, including veno-occlusive disease, long-term infertility and secondary malignancies.

We look forward to collaborating with NIAID on this Phase 1/2 clinical trial, which should provide important information about the potential of JSP191 as a safer and more effective conditioning agent for patients with CGD undergoing hematopoietic stem cell transplant, said Kevin N. Heller, M.D., Executive Vice President, Research and Development, of Jasper Therapeutics. Through this clinical trial agreement with NIAID, as well as others with the National Institutes of Health and academic centers, we are continuing to develop JSP191 for additional pretransplant conditioning regimens beyond severe combined immunodeficiency and acute myeloid leukemia/myelodysplastic syndromes, which have demonstrated safety and efficacy in early-stage clinical trials to date.

About JSP191

JSP191 is a first-in-class humanized monoclonal antibody in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow, creating an empty space for donor or gene-corrected transplanted stem cells to engraft. While hematopoietic cell transplantation can be curative for patients, its use is limited because standard high dose myeloablative conditioning is associated with severe toxicities and standard low dose conditioning has limited efficacy. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients. It is currently enrolling in two clinical trials for acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) and severe combined immunodeficiency (SCID) and is scheduled to begin enrollment in three additional studies in 2021 for severe autoimmune disease, sickle cell disease and Fanconi anemia patients undergoing hematopoietic cell transplantation.

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, a first-in-class anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplantation. It is designed to enable safer and more effective curative allogeneic and autologous hematopoietic cell transplants and gene therapies. In parallel, Jasper Therapeutics is advancing its preclinical engineered hematopoietic stem cell (eHSC) platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

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Jasper Therapeutics Announces New Clinical Trial with the National Institute of Allergy and Infectious Diseases to Evaluate JSP191 in Chronic...

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics Announces New Clinical Trial with the National Institute of Allergy and Infectious Diseases to Evaluate JSP191 in Chronic… | May 28th, 2021

KILLEEN, TX As blankets of snow covered the frigid ground and ice sheets laid atop of pavement, Michael or MJ Dixon was due for a sports physical at his normal pediatrician.

The doctor gave him a clearance, Chaundra Dixon, his mother explained. [The doctor] gave him a clearance and said, oh, he's healthy. He's fine.

MJ was used to getting hurt.

As a basketball, football, baseball and tennis star, its only a matter of time before one accumulates bruises and sore muscles.

However, MJ kept saying he was hurt.

His mom was convinced it was just growing pains, and so the duo worked on his stretching.

Until February 24, 2021.

She was at work on Fort Hood when MJs babysitter gave her a call.

She was just like, 'hey, I think you need to come home and get Michael, we need to get him to the hospital,' she recalled, as tears built up in her eyes thinking back to that day. He's crying non stop; he's saying he can't walk.

The panicked mother immediately picked up her son from their Killeen home and braved the icy road conditions, making it to Baylor Scott and White before EMS got to her house.

As they arrived at the hospital, they were met with COVID-19 tests. From there, physicians tested MJ for the basics, which all looked OK.

It wasnt until they ran blood work and found an abnormal amount of white blood cells in MJs body when they determined it was leukemia

About seven o'clock that night, I will never forget that, Dixon said. He was like, you're a great mom and I'm sorry, that I have to tell you, your son has leukemia, and I said leukemia? I lost it.

Living in this new reality brought on by his cancer, MJ and his family began looking for bone marrow donors.

The problem? He has less than a 25% chance of finding one due to his ethnicity.

http://www.bethematch.org

This is simply because we don't have the donor pool to pull from, Tressa Malone, a spokesperson with the Be The Match organization said. What that means is, we just need more people to join the registry. It's as simple as that.

Once you register to see if you can become a match, Malone explained that the following procedures are quite simple.

She said that if you match with a patient in need, 80% of their matches donate in a process similar to donating plasma.

You go and they take out the blood, separate the cells they need, then put it back in you.

She explained that this process is usually 3-4 hours.

The second procedure to donate is by retrieving the blood near your pelvic bone, the doctors separate the stem cells, all while youre under anesthesia.

Dr. Amy Mersiovsky, the director of nursing at Texas A&M Central Texas explained that she spent countless days caring for young kids with cancer as a pediatric nurse.

Realizing the low odds African Americans face when it comes to these donors, she explained that shes not necessarily surprised after the generations of mistrust that community typically has toward the medical field.

However, the Dixons dont go down without a fight because they know God is on their side.

Now, the family organizes bone marrow drives not only here in Central Texas, but across the county, hoping to find MJ a donor or anyone whos walking the same journey the 9-year-old boy is.

The family has set up a GoFundMe page to cover various expenses, and to see if you can be a match, you can text MJ to 61474 and a swab kit will be sent to your home.

To follow along with MJ's story, head over to his Facebook page.

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Killeen boy with leukemia needs a bone marrow donor, but the odds of finding one are slim - KXXV News Channel 25

Bone Marrow Stem Cells Comments Off on Killeen boy with leukemia needs a bone marrow donor, but the odds of finding one are slim – KXXV News Channel 25 | May 28th, 2021

For many years now, the topic of senescent cells has been the subject of plenty of research work. Back in the 1960s the Hayflick limit was noticed in cell culture: there was an apparent limit to the number of cell divisions that could take place before the cells just sort of stalled out. For human fibroblasts, that kicks in at around fifty divisions. Over time it was worked out that a primary mechanism involved is the shortening of telomeres with each cell division, specialized nucleotide sequences out at the ends of the chromosomes, and this cellular clock phenomenon has been making its way into the public consciousness ever since.

Its strange to think, but before these experiments human cells were considered to be more or less immortal and capable of unlimited numbers of divisions. Now, there are cells like that, but that (outside of some stem cell populations and a few other special cases) is a very short working definition of cancer. Those cells do indeed seem to be able to carry on for as long as conditions permit which in the artificial world of cell culture labs, means apparently forever. Henrietta Lacks died in 1951, but HeLa cells are still with us, and can be all too vigorous when they contaminate other lines. Tumor cells can pile up mutations that will make them die off, but short of that the jams have indeed been kicked out.

Its gradually become apparent that many aging or damaged tissues have a (sometimes substantial) population of cells that have reached their limit. Theyre alive and metabolically active but not really contributing much, in a stage of permanent growth arrest. Cellular senescence is a complex phenomenon, but its importance in aging, cancer, and tissue damaged by other factors (radiation, oxygen stress, etc.) is by now undeniable. Many of these non-aging states can be traced back to early telomere damage by other mechanisms, emphasizing that as a key countdown mechanism. But its clear that senescent have a different secretory profile (cytokines, growth factors and more) from the more vigorous cells around them and a number of other protein expression differences that can be used the characterize them.

Naturally enough, thoughts have turned to targeting such cells for therapy. There are a couple of very easy-to-picture hypotheses: first, could you keep telomeres from shortening (or shortening so much) and therefore keep cells in a non-senescent state for longer, potentially delaying biological aging? And second, could you somehow target cells that have already become senescent, and would doing so improve the health of the surrounding tissue? Though pretty obvious ideas, both of these are still very much in play. For now, Im going to talk about the second one, in light of a new paper.

That ones on the kidney. Younger people can regain some kidney function after an injury, but that ability goes down with aging, as youd imagine. It also goes down in states of chronic kidney disease, or after radiation damage. This new paper shows that targeting and removing senescent cells actually starts to reverse this phenotype once youve done that, the kidney tissue after injury shows increased function, increased regenerative ability, and less development of fibrosis. This is demonstrated both in aged tissue and in younger tissue exposed to radiation damage, in human cell culture and in mouse animal models.

You may well ask: how exactly does one target senescent cells? That takes us to ABT-263 (navitoclax), shown at right. This rather hefty molecule is part of a series of AbbVie protein-protein inhibitors for the Bcl-2 (B-cell-lymphoma) family. There are several of those, and navitoclax inhibits the function of Bcl-2, Bcl-xL, and Bcl-w. All of these proteins are intimately tied up in the pathways of apoptosis, programmed cell death, which is another monstrously huge pathway all its own. But one of the questions about senescent cells is why they dont go down some apoptotic pathway and just fall on their on cellular swords, instead of hanging around forever gumming up the works.

This one, like the others in its class, was developed to cause this to happen to tumor cells as an adjunct to other types of chemotherapy, but these have also turned out to be useful against senescent cells (although not all types of them). Similar to the kidney results reported in the new paper linked above, there have been reports in lung, CNS, muscle and other tissues of broadly similar enhancements (many of these summarized in this paper). So at this point you might be wondering why we dont just go ahead and put these things into the water supply already.

Theres a problem, unfortunately. It was clear from the clinical studies of the AbbVie compounds that platelet effects were dose-limiting. Cells in that pathway are sensitive to messing with these apoptosis pathways, and while you might be able to deal with that side effect in a chemotherapy situation, it doesnt exactly make for a good-for-what-ails-you drug. Navitoclax has alsorecently been shown to have profoundly bad effects on bone density and deposition, which is the exact opposite of what youd want for an aging population.

AbbVies next generation of such compounds, though, includes venetoclax, at right, also a lunker of a molecule and now approved for several types of leukemia. It still has platelet effects, but they arent nearly as disastrous as with navitoclax, thanks to deliberately lower binding to Bcl-xL. That also makes it a bit less of a mighty sword across senescent cell types for example, it appears that you need that pathway for activity against glioblastoma cells. But it has been reported to show strong protective effects against the development of Type I diabetes through the elimination of senescent cells in the islets of Langerhans. Meanwhile, other groups are looking at turning these ligands into targeted protein degraders, which (at least in some cases) seems to decrease the platelet problems and increase senolytic activity.

And before leaving the topic, it has to be noted that there are plenty of other ways to target these cells other than the Bcl pathway (although that one seems to be one of the most developed so far). What can I say? Im 59, and I doubtless have more senescent cells than I want or need, so I (and plenty of others) are interested in the idea. The whole cellular senescence pathway presumably developed as a way to avoid slipping into a tumor phenotype the more cellular divisions, the greater the chance of something going wrong along the way. Its a tradeoff, and evolution seems more than willing to shortchange older members of the species who have generally passed on their genes to all the offspring that theyre going to. But humans have other goals. We are looking at a rather rapidly aging planet, if current demographic trends hold up, and it would be extremely desirable to have that associated with less of a disease burden. Can we split the difference?

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Clearing Cellular Dead Wood | In the Pipeline - Science Magazine

Bone Marrow Stem Cells Comments Off on Clearing Cellular Dead Wood | In the Pipeline – Science Magazine | May 28th, 2021

REGULATED INFORMATION

Strong clinical progress especially in JTA-004 Phase III study thanks to high patient compliance and retention

Process development partnership and appointment of cell therapy expert Anthony Ting as CSO to further strengthen product pipeline

Gosselies, Belgium, 26May 2021, 7am CEST BONE THERAPEUTICS (Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, today announces its business update for the first quarter, ended 31 March 2021.

Bone Therapeutics has continued the strong momentum into 2021, said Miguel Forte, MD, PhD, CEO of Bone Therapeutics. Bone Therapeutics mid-late stage clinical programs continue to advance largely on schedule, including the Phase IIb trial of the allogenic cell therapy platform ALLOB in difficult-to-heal tibial fractures and the Phase III trial of the enhanced viscosupplement JTA-004 in knee osteoarthritic pain. Alongside this, Bone Therapeutics has strengthened its manufacturing and R&D capabilities by signing a process development partnership with Rigenerand. It has also appointed the industry veteran Tony Ting as our new Chief Scientific Officer. Building on these achievements, Bone Therapeutics will be able to continue significant clinical and commercial advancements as we move towards the topline data of our JTA-004 Phase III study; a potential key inflection point for Bone Therapeutics.

Operational highlights

Financial highlights

Outlook for the remainder of 2021

(1) Unaudited number

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a, diversified portfolio of cell and biologic therapies at different stages ranging from pre-clinical programs in immunomodulation to mid-to-late stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf next-generation improved viscosupplement, JTA-004, which is currently in Phase III development for the treatment of pain in knee osteoarthritis. Consisting of a unique combination of plasma proteins, hyaluronic acid - a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain and inflammation. Positive Phase IIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company has initiated patient recruitment for the Phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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Bone Therapeutics Provides First Quarter 2021 Business Update - GlobeNewswire

Bone Marrow Stem Cells Comments Off on Bone Therapeutics Provides First Quarter 2021 Business Update – GlobeNewswire | May 28th, 2021

A five-year-old boy has returned from New York where he is taking part in a pioneering medical trial aimed at preventing his cancer from returning.

Oliver Stephenson from West Yorkshire was given the all-clear earlier this year after battling neuroblastoma a rare cancer originating from immature nerve cells throughout 2020.

His family crowdfunded 270,000 for treatment as the schoolboy underwent chemotherapy, surgery, stem cell treatment and a bone marrow transplant.

At one point, Oliver and his dad James had to isolate together in a 15sqft hospital room for seven weeks due to the coronavirus pandemic.

Oliver has spent the past month at New York's Memorial Sloan Kettering Cancer Center, where he is on a clinical trial vaccine called Bivalent.

It is hoped the treatment will train his immune system to identify and destroy neuroblastoma cells lurking in his body to prevent the disease from returning.

The vaccine, which costs 210,000, will require Oliver to make four more trips to the US this year.

He returned from the four-week trip to New York around a week ago with his mum Laura, dad James and little brother Alfie.

Mrs Stephenson said: "Everything went great. The doctors were all amazing and Oliver has responded well so far.

"It is a clinical trial so we don't know what will happen but we are hoping that this will prevent Oliver from suffering as he has done again.

"After everything he has been through it feels great to be on a positive track."

She added the treatment was "quick and easy", explaining Oliver had three vaccines and that, other than some discomfort, he had no obvious side effects.

Due to the length of their stay, Mrs Stephenson said the family were able to make a holiday out of the trip.

She added: "Oliver and Alfie had a brilliant time in New York, it was amazing.

"Because of the pandemic everywhere was really quiet, which meant we felt very safe all the time and didn't have to queue for anything."

The pioneering treatment comes almost 18 months after Oliver was diagnosed with neuroblastoma, which affects around 100 children annually.

The coronavirus pandemic complicated the family's ordeal as Oliver and his dad had to isolate together in hospital during chemotherapy.

Mr Stephenson was at his son's bedside throughout, but the rest of his family were unable to visit due to restrictions and had to make do with video calls.

Crowdfunding pages were set up to help the family pay for treatment once options on the NHS were exhausted, as neuroblastoma has a significant chance of returning.

Mrs Stephenson added: "The incredible support and donations not just from our friends and family but around the world has been overwhelming.

"We are so grateful to everyone who has helped.

"It's been a really difficult year for us and back in 2020 Oliver's prognosis wasn't good at all.

"But he has battled through everything is doing well now, he's fit and strong and even back at school.

Despite Oliver getting the all-clear, figures show 60% of people who recovered from neuroblastoma end up relapsing.

Mrs Stephenson said: "We want to everything we can to stop that happening."

Throughout Oliver's treatment, his family has been supported by the Solving Kids Cancer charity.

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Five-year-old boy returns home after first round of cancer treatment in New York - Surrey Live

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bluebird bios cerebral adrenoleukodystrophy (CALD) gene therapy Skysona has moved closer towards EU approval after gaining a positive opinion from the European Medicines Agencys Committee for Medicinal Products for Human Use (CHMP).

The CHMP has recommended marketing authorisation for Skysona (elivaldogene autotemcel, Lenti-D) for the early treatment of CALD in patients under 18 years old with an ABCD1 genetic mutations, and who do not have a matched sibling haematopoietic stem cell (HSC) donor.

bluebird bio's Skysona is a potential one-time gene therapy designed to add functional copies of the ABCD1 gene into a patients hematopoietic stem cells.

Once this functional gene is added to a CALD patients stem cells, the patient's body can produce the adrenoleukodystrophy protein (ALDP), which is believed to allow for the breakdown of very-long-chain fatty acids that build up to toxic levels in the brain.

CALD is a progressive and fatal neurodegenerative disease that overwhelmingly affects males. It involves the breakdown of myelin the protective sheath of nerve cells in the brain that is responsible for muscle control and thinking.

The condition is caused by mutations in the ABCD1 gene that affect the production of ALDP which eventually causes damage to the adrenal cortex and white matter of the brain and spinal cord.

Currently, the only treatment for the disease is a stem cell transplant, although this carries a significant risk from the high-dose chemotherapy used to prepare patients for the procedure.

Other complications include graft-versus-host (GvHD) disease, which occurs when the transplanted cells recognise the recipients cells as foreign and attack them.

In the phase 2/3 Starbeam study evaluating Skysona, 90% of CALD patients met the month 24 major functional disability- (MFD) free survival endpoint as of the last data cutoff date.

MFDs are the six severe disabilities commonly attributed to CALD, which have the most severe effect on a patients ability to function independently.

In addition, 26 out of 28 evaluable patients maintained a neurologic function score (NFS) less than or equal to one until month 24, with 24 of those patients having no change in their NFS.

The CHMPs positive opinion is now due to be reviewed by the European Commission, with a final decision for Skysona expected in mid-2021.

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NEARLY 10,000 has been raised in less than a week to help pay for a Dunfermline mum to have life-changing treatment in Russia.

Lynda Hogg was first diagnosed with Primary Progressive Multiple Sclerosis (PPMS) seven years ago and since then, she has seen her health deteriorate.

She has been forced to give up her job as a theatre nurse at Queen Margaret Hospital and faces a daily battle with pain from a condition for which there is no cure and no treatment on the NHS.

Lynda, 58, and her family are now pinning their hopes on travelling to Russia for Hematopoietic Stem Cell Transplantation which, it is hoped, will stop the progression of her MS.

Within a week of being set up, a GoFundMe page has already raised nearly a quarter of the required 45,000, something which Lynda said she was overwhelmed and humbled by.

It was my son who said how do you feel in 10 years time if you are wheelchair-bound knowing you had this opportunity and didnt take it? she explained.

We have considered selling the house if we have to.

Daughter Popsi is hopeful that the GoFundMe page will mean such a drastic step is not necessary.

Before the GoFundMe, these were all considerations, she said. Shall we sell the house, will my dad have to give up his job and become a carer?

After we found out about this treatment years ago, I dont think we ever really considered it a possibility. It has been quite tough. I have three brothers. Speaking on behalf of the younger ones, I want them to remember them as I remember her, full of life.

This treatment is kind of a possibility that it would not get any worse. It is a pipe dream. We never thought it could happen. The support and kindness of others has been so touching.

Multiple Sclerosis (MS) is a disabling disease of the brain and spinal cord which results in muscle and nerve damage, ongoing pain and fatigue.

Since her diagnosis, Lynda, who is married to Murray and has four children, Adam, 29, Popsi, 23, Mitchell, 18, and Charlie, 15, has seen her health go downhill with her mobility decreasing.

She has been shocked at the lack of available medication.

Basically, I get co-codamol, she said. Progressive Primary MS is the worst form of it. There is no treatment and there is really little in the way of emotional support. It is not a fault of the NHS. There is nothing and there needs to be something.

PPMS is 15 per cent of people diagnosed. It is horrible to think there is nothing out there for them.

Trials for the treatment which Lynda hopes to have in Russia have taken place in the UK but, to date, are not available on the NHS for patients like herself.

They give you medication to increase the quality of stem cells. They are harvested and then you are given chemo then the stem cells are reintroduced to you. They can stop MS in its tracks. It will stop the progression. It wont give you functions back.

Even just to stop it progressing; I can cope with the disabilities I have but I dont know if I can cope with them moving forward and getting worse.

Popsi and her siblings are planning to hold further fundraisers when coronavirus restrictions allow while also raising awareness of MS.

We have had to watch our mum struggle with the disease and battle with pain every day, she added. We feel that its time to give back to our mum, and everything that she has done for us over the years.

Anyone wanting to help can do so by visiting https://gofund.me/61401f6e.

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NEW ORLEANS (WGNO) Several contract workers were burned during a gas well explosion on Belle Isle along the Gulf of Mexico on Tuesday.

Of those wounded, three were reported taken to University Medical Center the regions only Level I verified trauma and verified burn center.

According to Dr. Jeffrey Carter, Medical Director of the UMC Burn Center and professor of surgery at LSU Health-New Orleans, speed is of the essence when it comes to successful treatment of burn victims.

At 2:56 pm, Acadian received a report of a well fire. We sent 4 helicopters and 5 ground units to Morgan City (LA). We transported two patients by air (1 to NOLA and 1 to Lafayette area) and 2 patients by ground (both to NOLA)

Delays in medical treatment can result in increased amounts of resuscitation, increased length of hospital stays, increased infection risks and increased kidney problems.

Its important to realize here in Louisiana, we have a fair number of risks. About 85 percent of all hazardous waste travels through our port or rail here in New Orleans, said Dr. Carter.

There are over 3,000 rigs, gas and pipeline areas here that are at risk along the gulf. When we have injuries that occur from industrial accidents, what we find is that the mortality is increased by about 20 percent if there is a delay of about two hours in transporting the patient to a center where they can get definitive care.

Dr. Carter says being an academic medical research center, UMC is able to offer the latest technology in the treatment of severe burns.

On the forefront of burn care is the use of RECELLs spray-on skin by Avita Medical, in which the doctors take a small portion of the patients own skin, dissolve it and pull the stem cells, and then -apply it at the time of surgery.

Dr. Carter explained and demonstrated the use of RECELL during a Zoom interview with WGNOs Aaron S. Lee on Wednesday.

He also discussed how the use of artificial intelligence will soon revolutionize how burn victims are treated and how quickly they recover.

That video clip can be seen below:

According to Dr. Carter, half of his patients suffer burns to their hands and face as these are areas not covered, especially in the deep south. This can be worrisome to the victim after recovery as those are places people notice first when interacting with another person.

Not to mention, the face is extremely complex with the amount of movement and how it changes over time.

The use of RECELL on a burn victims face is making skin grafts a thing of the past.

A skin graft is like putting a piece of plywood on your roof when it has a hole in it, explained Dr. Carter. It doesnt look the same. It doesnt act the same. It doesnt behave the same.

While its OK for some types of injuries, said Dr, Carter, its not necessarily the best thing.

Dr. Carter goes on to explain the benefits of using of the RECELL system and ultimately allowing burn patients to heal themselves using their own cells during recovery.

The FDA is considering RECELL for pediatric burns, with Dr. Carter serving as one of the clinical trial investigators.

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Burn victims like the wounded Belle Isle contractors in good hands at UMC, spray-on skin at forefront of care - ArkLaTexHomepage

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Aging is the ultimate risk factor for most diseases, such as cancer, neurodegenerative, cardiovascular, diabetes, degenerative fibrosis and many others. When we are young, we are typically healthy, despite a predisposition that will lead inevitably to a specific degenerative condition. However, the degenerative processes do not kick in until a certain age, when we are older. It looks like when we are younger, the body can compensate cumulative stress and damage caused to our cells in the tissues, allowing to maintain that equilibrium, called homeostasis, that keeps our organs functional and healthy. However, over time this buffering capacity becomes thinner and thinner, until things wear off: our tissues stop working as they used to. These changes are typically caused by an initial small number of rare but bad cells, that progressively increase over time, causing additional damage to the good cells that eventually stop working efficiently, causing a vicious cycle. Eventually the bad cells take over leading to the onset of a disease.

Our body is equipped with a number or regenerative and healing functions. Some are intrinsic in every cell, such as DNA repair mechanisms that are triggered when something compromises the integrity of our genomic structures. These are important functions that enable a cell, for example when it replicates, to repair errors and other damages that might have happened to our DNA. For example, two large proteins called ATM and ATR, involved in the cellular response to DNA damage, are responsible to maintain genomic instability caused by intrinsic and external DNA-damaging agents, such as UV light or various chemicals and toxins. A lack of functions of these proteins results in progressive neurodegeneration, immunodeficiency, predisposition to malignancy or radiation sensitivity. Mutations on the genes encoding these proteins can cause premature aging and premature development of these diseases, but this occurs also naturally, over time.

Cells also have an intrinsic immune system, producing factors called interferons employed by the cells as antiviral agents and to modulate other immune functions. It can be triggers by a viral infection so when a cell is infected will release interferons, protecting the neighbor cells against potential infection. Interferons can also suppress growth of blood vessels preventing tumors to get nutrients and growing. They can also activate immune cells so they can better fight viruses, tumors and others agents. Unfortunately, an age-related decline or impaired innate interferon functions in the cells results in a number of negative consequences in the body, such as increased susceptibility of the elderly to infections, tumors and damage.

In the body there are several cell types responsible to keep the tissues in check. The immune system is specialized to recognize remove and remember damaging agents. Those could be external, such as virus, bacteria or parasites, or internal, such as tumorigenic cells or senescent cells (see below). The immune system is a very sophisticated network of cell types, intercommunicating with each other to maintain the body clean from damaging factors. As we age the immune system also ages and loses capacity to recognize or responding to these damaging agents. It also become exhausted by an increasing chronic inflammation that progressively accumulate as we age, phenomenon also called inflammaging.

Another important repairing mechanism is the regenerative tissue functions, driven by the stem cells. Those cells are progenitor cells, often dormant in a quiescent state in the tissue and waiting to be activated by some damage. Stem cells are critical because once activated they can generate a progeny of daughter cells capable of re-growing the damaged tissue back to its original structure and function. Stem cells have another important function: they can regenerate themselves, in a process called self-renewal. This is important so that the new repaired tissue can repeat the process if a new damage occurs. The regenerative capacity of our body is remarkable, allowing our tissues to keep their integrity, health and functions. However, over time also stem cells age or respond to the aged microenvironment where they live (called the niche), and they become less efficient to repair tissues or to self-renewing. As a result, our tissues change, become atrophic, fibrotic or dysfunctional leading eventually to diseases.

In regenerative medicine, the application of stem cells resulted of the generation of multiple new therapeutic opportunities. A promising area uses stem cells to generate bioengineering strategies to grow new tissues in a petri dish to be then transplanted in the body to repair damaged tissues. Some applications are already in clinical use, such as for skin grafts. Many others are on their way, either in preclinical development or in clinical trials for many different tissue types and for different clinical indications.

Another promising stem cells application is the direct transplantation into damaged tissues, where they can grow and engraft repairing. However, as we age stem cells become less efficient. What if we If we could rejuvenate them? We could restore their capacity to repair our tissues and maintain homeostasis. Promising and exciting strategies are advancing in that direction. For example, we and others showed that it is possible to reprogram epigenetically a cell so it can become the younger and healthier version of itself (Sarkar et al., 2020). This is a mechanism that every cell has encoded in its DNA, but normally works only in the germline (the sperm and the egg) during the embryogenesis to make sure that the cellular clock is turned back to zero, before initiating the cellular programs to generate the embryo. This important for example to prevent making old newborn babies. This intrinsic rejuvenative mechanism is locked in the other somatic cells of the body. We found it is possible to re-activate it transiently and safely, without changing the identity of the cell, enabling to push back the cellular clock of aged human cells to make them healthier and restore their functions. These technologies are under development to be translated into therapeutics with the promise that one day could rejuvenate the aged cells in the body so they can become the younger version of themselves, repeating the process over time when needed.

Among many of the drivers of the aging process, there is one that seems to stands out as the lower hanging fruit among the emerging space of the longevity therapeutics. This is cellular senescence. Every damage that occurs to the cells in our body can push the cells to stop what they are doing and activate a safety mechanism that locks them into an arrested state called cellular senescence. Senescent cells cannot replicate anymore preventing them to cause additional damage, such as becoming cancer cells. All sort of damage can trigger this response leading to cellular senescence such as, oxidative stress, mitochondrial dysfunctions, DNA damage, viral infection, cigarette smoking, pollutions, chemicals, etc. They all can induce that safety lock and push damage cells to become senescent.

Senescent cells dont die easily but they stick around in the tissue, accumulating slowly over time. Importantly, cellular senescence is a pleiotropic mechanism, meaning it can be both good or bad. When we are young, we can efficiently get rid of senescent cells. The body uses them positively such as for tissue repair, wound healing or tissue remodeling. However, as we age, and our immune system ages (partially trough cellular senescence, a phenomenon called immune-senescence), our body become less efficient in removing senescent cells, which then start to accumulate.

Being able to make a new generation of drugs that are very selective for senescent cells, will enable the promise to achieve rejuvenative clinical results in humans similarly to what we found in preclinical results. On that end, we recently published a targeted strategy with the goal to advance the field in that direction (Doan et al., 2020). Using a prodrug, we engineered a small molecule to generate a selective senolytic compound to develop a targeted therapy. This prodrug is inactive in non-senescent cells but activated by senescent cells, taking advantage of an enzymatic function of those cells. In geriatric mice this prodrug showed to be well tolerated but also efficacious to clear senescent cells, resulting in restored cognitive functions, muscle functions, stem cells functions, vitality and overall health. As we advance senolytic drugs to the clinic to treat age-related diseases, it is very important to be mindful that elderly individuals, who are frail, with co-morbidities and exposed to multiple medications, will not well tolerate drugs that are not safe and effective. Importantly, not all senescent cells are the same. They are rare, interspersed in the tissues but are also very heterogeneous. Being able to hit the right senescent cells, in the right diseased tissue will be key to enable effective therapies. Developing drugs that are very potent, selective and potent and safe will be pivotal.

The longevity therapeutics space is emerging, but is already disrupting the medical industry. The goal of longevity therapeutics is not just to add years to life, extending lifespan. The true goal is to add life to years and extend health span. A target that gets closer every day.

Marco Quarta is CEO, Rubedo Life Sciences.

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CRANFORD, N.J., May 25, 2021 /PRNewswire/ --Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR), a biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products with a focus on anti-infective products in adjunct cancer care, unique prescription products and stem cell therapy, today announced that it has received the Best Poster Award at the prestigious International Society for Cell and Gene Therapy (ISCT) 2021 Annual Meeting.

The poster, titled "Novel Induced-Mesenchymal Stem Cells (i-MSCs) Attenuate Severity of ARDS in Septic Sheep," will be presented today, May 25, 2021 by Dr. Perenlei Enkhbaatar, Professor and Director of the Translational Intensive Care Unit at The University of Texas Medical Branch.

"The ISCT annual meeting brings together the brightest minds in cell and gene therapy and highlights cutting edge research in the field," stated Dr. Myron Czuczman, Chief Medical Officer and Executive Vice President of Citius. "We are honored to be selected for the Best Poster Award from among this distinguished peer group. The interim results demonstrate a marked improvement in i-MSC treated animals over control animals in key clinical parameters including: improved oxygenation, less systemic shock, and reduced bacterial burden and vascular injury to the lungs. We are encouraged by the data and welcome the support and engagement of the scientific research community," concluded Dr. Czuczman.

Myron Holubiak, President and Chief Executive Officer of Citius added, "We are grateful to be recognized by our peers for this award as we advance our novel stem cell program for the treatment of ARDS. In parallel to the expansion of our proof-of-concept ARDS sheep study, we are following guidance from the U.S. Food and Drug Administration (FDA) in the development of a cGMP Master Cell Bank of i-MSCs. I am pleased to report that we have completed the development of an i-MSC Accession Cell Bank (ACB) which is to serve as the basis for a scalable cGMP compliant manufacturing capability to support all of our planned pre-clinical and clinical trials. Compared with donor-derived cells that require a continuous supply of new donors, we believe our i-MSCs,derived from a single clonal induced pluripotent stem cell (iPSC), offer multiple advantages including consistent and scalable manufacturing and a potentially limitless supply of i-MSCs to meet our future needs. Moreover, we believe that our i-MSC stem cell program has the potential to meaningfully impact the treatment of ARDS and we appreciate the recognition received from the cell and gene therapy community as we advance our program."

Citius' i-MSCs are derived from iPSCs originating from a qualified single-donor dermal fibroblast, resulting in one homogeneous, validated source for all future cells. A patented synthetic, non-immunogenic mRNA high efficiency cell reprogramming technique is applied to create a clonal iPSC Master Cell Bank from which our i-MSCs are differentiated and expanded to create an i-MSC Accession Cell Bank. Citius has completed the development of its i-MSC ACB and is currently testing (as per FDA guidance) and expanding the cells to create an allogeneic cGMP i-MSC Master Cell Bank to support all future i-MSC needs.

The poster will be available to conference attendees via the conference website. The poster will be available on Citius' website once the event commences.

Conference Details:

Abstract Title:

"Novel Induced-Mesenchymal Stem Cells (i-MSCs) Attenuate Severity of ARDS in Septic Sheep"

Authors:

K. Hashimoto, N. Bazhanov, P. Enkhbaatar, M. Angel, A. Lader, M. Czuczman, and M. Matthay

Abstract Number:

100

Date and Time:

May 25, 2021

Session I

12:30 2:00 PM EDT

Session II

8:00 9:30 PM EDT

About Acute Respiratory Distress Syndrome (ARDS)

ARDS is an inflammatory process leading to build-up of fluid in the lungs and respiratory failure. It can occur due to infection, trauma and inhalation of noxious substances. ARDS accounts for approximately 10% of all ICU admissions and almost 25% of patients requiring mechanical ventilation. Survivors of ARDS are often left with severe long-term illness and disability. ARDS is a frequent complication of patients with COVID-19. ARDS is sometimes initially diagnosed as pneumonia or pulmonary edema (fluid in the lungs from heart disease). Symptoms of ARDS include shortness of breath, rapid breathing and heart rate, chest pain (particularly while inhaling), and bluish skin coloration. Among those who survive ARDS, a decreased quality of life is relatively common.

About Citius Pharmaceuticals, Inc.

Citius is a late-stage biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products, with a focus on anti-infectives in adjunct cancer care, unique prescription products, and stem cell therapy. The Company's lead product candidate, Mino-Lok, an antibiotic lock solution for the treatment of patients with catheter-related bloodstream infections (CRBSIs), is currently enrolling patients in a Phase 3 pivotal superiority trial. Mino-Lok was granted Fast Track designation by the U.S. Food and Drug Administration (FDA). Through its subsidiary, NoveCite, Inc., Citius is developing a novel proprietary mesenchymal stem cell treatment derived from induced pluripotent stem cells (iPSCs) for acute respiratory conditions, with a near-term focus on Acute Respiratory Distress Syndrome (ARDS) associated with COVID-19. For more information, please visit http://www.citiuspharma.com.

Safe Harbor

This press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "plan," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated are: risks relating to the results of research and development activities, including those for our NoveCite stem cell therapy; uncertainties relating to preclinical and clinical testing; the early stage of products under development; our dependence on third-party suppliers; our ability to successfully undertake and complete clinical trials and the results from those trials for our product candidates; the estimated markets for our product candidates and the acceptance thereof by any market; the ability of our product candidates to impact the quality of life of our target patient populations; our need for substantial additional funds; market and other conditions; risks related to our growth strategy; patent and intellectual property matters; our ability to attract, integrate, and retain key personnel; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; our ability to identify, acquire, close and integrate product candidates and companies successfully and on a timely basis; our ability to procure cGMP commercial-scale supply; government regulation; competition; as well as other risks described in our SEC filings. These risks have been and may be further impacted by Covid-19. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission ("SEC") filings which are available on the SEC's website at http://www.sec.gov, including in our Annual Report on Form 10-K for the year ended September 30, 2020, filed with the SEC on December 16, 2020 and updated by our subsequent filings with the SEC. These forward-looking statements speak only as of the date hereof, and we expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Investor Relations for Citius Pharmaceuticals:

Andrew ScottVice President, Special ProjectsT: 908-967-6677 x105E: [emailprotected]

Ilanit AllenVice President, Corporate Communications and Investor RelationsT: 908-967-6677 x113E: [emailprotected]

SOURCE Citius Pharmaceuticals, Inc.

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Citius Pharmaceuticals Selected to Receive Best Poster Award at the International Society for Cell and Gene Therapy 2021 Annual Meeting - PRNewswire

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If you have certain types of cancer, your doctor might suggest Keytruda (pembrolizumab) as a treatment option for you.

Keytruda is a prescription medication thats used to treat certain advanced forms of the following kinds of cancer in adults and some children:

Keytruda can also be used to treat these kinds of cancer in some children as well as adults:

Keytruda comes as a solution a healthcare professional injects into your vein over a period of time. This is called an intravenous infusion.

Keytruda is a biologic, which is a treatment made from parts of living organisms. It isnt available in a biosimilar form. Biosimilars are like generic drugs. But unlike generics, which are made for non-biologic drugs, biosimilars are made for biologic drugs.

For more information about Keytruda, including details about its uses, see this in-depth article on the drug.

Like other drugs, Keytruda can cause mild and serious side effects. Keep reading to learn more.

Some people may experience mild or serious side effects during their Keytruda treatment. These side effects can vary depending on whether Keytruda is used alone or with other cancer drugs.

Examples of Keytrudas commonly reported side effects include:

* To learn more about this side effect, see Side effects explained below.

Read on to learn about other possible side effects of Keytruda.

Keytruda may cause mild side effects. These side effects can vary depending on whether Keytruda is used alone or with other cancer drugs.

Examples of mild side effects that have been reported with Keytruda include:

* To learn more about this side effect, see Side effects explained below.

In most cases, these side effects should be temporary. And some may be easily managed, too. But if you have any symptoms that are ongoing or that bother you, talk with your doctor or pharmacist. And dont stop using Keytruda unless your doctor tells you to.

Keytruda may cause mild side effects other than the ones listed above. See the Keytruda medication guide for more information.

Note: After the Food and Drug Administration (FDA) approves a drug, it tracks side effects of the medication. If youd like to notify the FDA about a side effect youve had with Keytruda, visit MedWatch.

Serious side effects may occur with Keytruda. These side effects can vary depending on whether Keytruda is used alone or with other cancer drugs.

Many of Keytrudas serious side effects happen because of an overactive immune system. These are called immune-mediated side effects, and they often cause inflammation (damage and swelling) to tissues. Examples include:

Other serious side effects that have been reported with Keytruda include:

* To learn more about this side effect, see Side effects explained below.

If you develop serious side effects while using Keytruda, call your doctor right away. If the side effects seem life threatening or if you think youre having a medical emergency, immediately call 911 or your local emergency number.

Get answers to some frequently asked questions about Keytrudas side effects.

In most cases, Keytrudas side effects should be temporary. Most should go away soon after you start or stop the drug.

But Keytruda can cause serious side effects that may lead to long-term problems. In some cases, these problems can take many weeks or months to resolve. Here are some examples, all of which cause inflammation (damage and swelling) in different parts of the body:

If you have questions about what to expect long term while using Keytruda, talk with your doctor or pharmacist. But dont stop using Keytruda unless your doctor recommends it.

Yes, in rare cases, Keytruda may cause serious eye side effects (sometimes called ocular side effects).

Examples of eye problems that may happen while using Keytruda include:

Symptoms of eye side effects from Keytruda will depend on the exact eye problem you have. But possible symptoms that may happen with one or both eyes include:

Tell your doctor right away if you have any symptoms of eye problems while using Keytruda.

Keytruda is prescribed to treat many types of cancer, including non-small cell lung cancer and small cell lung cancer. The side effects of Keytruda are expected to be the same regardless of the type of cancer its treating. For a full list of the cancers Keytruda is used to treat, see this in-depth article on the drug.

To learn more about possible side effects of Keytruda, see the What are the mild side effects of Keytruda? and What are the serious side effects of Keytruda? sections above.

If you have questions about what to expect when using Keytruda to treat lung cancer, talk with your doctor.

Yes, confusion is a possible side effect of Keytruda. In fact, confusion was a common side effect of Keytruda in studies of the drug.

Confusion can make you feel as though you cant think clearly. You may also have problems making decisions or focusing on a task. This side effect can also lead to abnormal or slurred speech.

Its important to remember that encephalitis (inflammation of your brain) may cause confusion. Encephalitis is a rare but serious side effect of Keytruda. For this reason, you should tell your doctor right away if you experience confusion while using Keytruda. Theyll likely check you for signs of encephalitis.

Learn more about some of the side effects Keytruda may cause.

Muscle pain or bone pain are common side effects of Keytruda.

You can relieve muscle or bone pain by:

Before using OTC drugs with Keytruda, talk with your doctor or pharmacist. And ask your doctor about other ways to relieve bothersome muscle or bone pain that Keytruda may cause.

In rare cases, some people may have hair loss while using Keytruda. In studies, hair loss was more common when Keytruda was used with chemotherapy drugs than when used alone.

Hair loss as a side effect of Keytruda is usually temporary. If you have hair loss from using Keytruda, your hair should start growing back several weeks after your last dose.

Cooling caps, which are caps designed to keep your scalp cold, might help prevent hair loss. Cooling caps lessen the blood flow to your scalp, which may decrease the effect of Keytruda or chemotherapy on your hair. Ask your doctor if a cooling cap is right for you.

When your hair does start to return, dont overuse hair styling tools that are harsh on hair. These include blow dryers and hair straighteners. You should also avoid bleaching or coloring your hair so it stays healthy enough to grow.

If you experience bothersome hair loss while using Keytruda, talk with your doctor about ways to help with this side effect.

You may have itchy skin or rash from using Keytruda. Itchy skin and mild rashes are common side effects of the drug.

In rare cases, Keytruda may also cause severe rashes and other skin reactions. These include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). With SJS and TEN, you have a rash along with painful sores on your eyes, genitals, mouth, or throat.

Here are a few tips for helping relieve itching and rash:

If you have a severe skin reaction to Keytruda, youll likely need treatment in a hospital. If you have severe skin peeling or blisters after using the drug, call 911 or your local emergency number right away. These may be signs of a serious skin reaction, which can be life threatening.

If youre concerned about your risk for a severe skin reaction from using Keytruda, talk with your doctor.

Like most drugs, Keytruda can cause an allergic reaction in some people.

Symptoms can be mild or serious and can include:

If you have mild symptoms of an allergic reaction, such as a mild rash, call your doctor right away. They may suggest an over-the-counter antihistamine you can take by mouth, such as diphenhydramine (Benadryl), or a product you can apply to your skin, such as hydrocortisone cream, to manage your symptoms.

If your doctor confirms you had a mild allergic reaction to Keytruda, theyll decide if you should continue using it.

If you have symptoms of a severe allergic reaction, such as swelling or trouble breathing, call 911 or your local emergency number right away. These symptoms could be life threatening and require immediate medical care.

If your doctor confirms you had a serious allergic reaction to Keytruda, they may have you switch to a different treatment.

During your Keytruda treatment, consider keeping notes on any side effects youre having. Then, you can share this information with your doctor. This is especially helpful to do when you first start taking new drugs or using a combination of treatments.

Your side effect notes can include things like:

Keeping notes and sharing them with your doctor will help your doctor learn more about how Keytruda affects you. And your doctor can use this information to adjust your treatment plan if needed.

Keytruda is used to treat certain types of cancer in some children. (For information about the cancers Keytruda can treat in children, see this detailed article on the drug.)

Most side effects that occur in children receiving Keytruda are similar to those that adults experience. However, some side effects of Keytruda are more common in children. These include:

Talk with your childs doctor about their risk for side effects from Keytruda.

Keytruda may not be right for you if you have certain medical conditions or other factors that affect your health. Talk with your doctor about your health history before you take Keytruda. Factors to consider include those in the list below.

Allergic reaction. If youve had an allergic reaction to Keytruda or any of its ingredients, you shouldnt take Keytruda. Ask your doctor what other medications are better options for you.

Receiving certain other treatments for multiple myeloma. Using Keytruda with certain other treatments for multiple myeloma can be fatal. (Multiple myeloma is a cancer that affects a type of white blood cell called a plasma cell.) Before using Keytruda, tell your doctor if youre taking any treatments for multiple myeloma.

Received an organ transplant. Before using Keytruda, tell your doctor if youve had an organ transplant. Keytruda can raise the risk for your immune system attacking the transplanted organ. If youve had a transplant, your doctor will tell you what symptoms of organ rejection you should watch for while using Keytruda.

Received or plan to receive a stem cell transplant. Before using Keytruda, tell your doctor if youve received stem cells from a donor in the past or plan to do so. You may be at a higher risk for graft-versus-host disease. This condition causes your immune system to attack the transplant stem cells. Talk with your doctor about whether Keytruda is safe for you to use.

It should be safe to drink alcohol while using Keytruda.

But be aware that alcohol can cause side effects that are similar to some of Keytrudas. These include diarrhea, fatigue (lack of energy), and nausea. If you drink alcohol during Keytruda treatment, it may make these side effects worse.

Talk with your doctor about the amount of alcohol thats safe for you to drink while using Keytruda.

You shouldnt use Keytruda while pregnant or breastfeeding.

Keytruda hasnt been studied during pregnancy. But based on how the drug works, Keytruda may cause harm to infants born to pregnant females* who used the drug during pregnancy.

For this reason, you should use birth control while taking Keytruda if you or your partner can become pregnant. And you should continue to use birth control for at least 4 months after your last dose.

It isnt known if Keytruda can pass into breast milk. To be safe, you shouldnt breastfeed while using Keytruda and for at least 4 months after your last dose.

Before starting Keytruda treatment, tell your doctor if youre pregnant or planning to become pregnant. Also tell them if youre breastfeeding or planning to breastfeed. They can discuss your options with you.

* In this article, we use the term female to refer to someones sex assigned at birth. For information about the difference between sex and gender, see this article.

Keytruda is a drug used to treat certain types of cancer in adults and some children.

Some people who use Keytruda may have mild side effects. Although rare, serious side effects can occur with Keytruda. Many of these happen because of an overactive immune system. Keep in mind that the side effects of Keytruda can vary depending on whether Keytruda is used alone or with other cancer drugs.

Talk with your doctor or pharmacist if you have questions about Keytrudas side effects. Here are a few questions you may want to ask:

Disclaimer: Healthline has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or other healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

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Skin Stem Cells Comments Off on Keytruda Side Effects: What They Are and How to Manage Them – Healthline | May 28th, 2021

Founded to meet the future protein demands of an expanding global population, Australias Magic Valley is developing cell-cultured lamb products including mince, strips, steaks and chops. With lambs currently slaughtered at an incredibly young age using traditional farming methods, its founder tells us this particular meat became the obvious choice for the companys first product range.

There is absolutely no need for the mass slaughter of animals for food and hopefully intensive animal agriculture will soon be a thing of the past

Vegconomist spoke with Founder Paul Bevan, who says that he had become frustrated by the pace of change and effectiveness of his own activism so he turned his attention to technology, specifically the development of slaughter-free cultured meat, beginning with lamb.

Utilising induced pluripotent stem-cells and FBS-free media, Magic Valley is able to grow real animal meat from animal cells, using animals such as Lucy, who Paul refers to as cell volunteers.

Eventually we would like to expand into developing cultured meat products for all other animal species

Lucy the lamb is our very special cell donor. From just a tiny skin biopsy less than 4mm in diameter we are able to generate an infinite number of muscle and fat cells without ever having to interfere with an animal again. That is one of the distinct advantages of our technology and using induced pluripotent stem cells.

Meanwhile, Lucy gets to live out the entirety of her natural life (up to 20 years of age) happy and unharmed, blissfully unaware that her cell donation has potentially saved the lives of billions of lambs that would otherwise have been slaughtered at just 6 months of age.

Magic Valleys team consisting of Australias leading scientists have extensive experience in both stem cell biology and livestock production. As part of its ambitions to become a leader in the field, the company also announced this week the onboarding of industry pioneer Dr. Sandhya Sriram, PhD, Co-Founder & CEO of the cell-based crustacean producers Shiok Meats, to its advisory board.

Eventually we would like to expand into developing cultured meat products for all other animal species that have traditionally been farmed for human consumption. With the advancement of this technology, there is absolutely no need for the mass slaughter of animals for food and hopefully intensive animal agriculture will soon be a thing of the past, Bevan commented to vegconomist.

Our immediate goal is to develop the safest, healthiest and tastiest cultured lamb products possible. We know that to be successful, cultured meat products have to become the obvious choice for consumers and that means taste, price & convenience are paramount. We know that ethical or environmental concerns alone are not enough to change consumer behaviour it has to be a better product.

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Australia's Magic Valley On How to Turn Cells From "Cell Volunteer" Lucy the Lamb Into Lamb Steaks and Chops - vegconomist - the vegan...

Skin Stem Cells Comments Off on Australia’s Magic Valley On How to Turn Cells From "Cell Volunteer" Lucy the Lamb Into Lamb Steaks and Chops – vegconomist – the vegan… | May 28th, 2021

DUBLIN--(BUSINESS WIRE)--The "Global Stem Cell Therapy Market by Type (Allogeneic, Autologous), Therapeutic Application (Musculoskeletal, Wound & Injury, CVD, Autoimmune & Inflammatory), Cell Source (Adipose tissue, Bone Marrow, Placenta/Umbilical Cord) - Forecasts to 2026" report has been added to ResearchAndMarkets.com's offering.

The global stem cell therapy market is projected to reach USD 401 million by 2026 from USD 187 million in 2021, at a CAGR of 16.5% during the forecast period.

Growth in this market is majorly driven by the increasing investment in stem cell research and the rising number of GMP-certified stem cell manufacturing plants. However, factors such as ethical concerns and the high cost of stem cell research and manufacturing process likely to hinder the growth of this market.

The allogeneic stem cell therapy segment accounted for the highest growth rate in the stem cell therapy market, by type, during the forecast period

The stem cell therapy market is segmented into allogeneic and autologous stem cell therapy. Allogeneic stem therapy segment accounted for the largest share of the stem cell therapy market. The large share of this segment can be attributed to the lesser complexities involved in manufacturing allogeneic-based therapies.

This segment is also expected to grow at the highest growth rate due to the increasing number of clinical trials in manufacturing allogeneic-based products.

Bone Marrow-derived MSCs segment accounted for the highest CAGR

Based on the cell source from which stem cells are obtained, the global stem cell therapy market is segmented into four sources. These include adipose tissue-derived MSCs (mesenchymal stem cells), bone marrow-derived MSCs, placenta/umbilical cord-derived MSCs, and other cell sources (which include human corneal epithelium stem cells, peripheral arterial-derived stem cells, and induced pluripotent stem cell lines).

The bone marrow-derived MSCs segment is expected to witness the highest growth rate during the forecast period, owing to an increasing number of clinical trials focused on bone marrow-derived cell therapies and the rising demand for these cells in blood-related disorders.

Asia Pacific: The fastest-growing country in the stem cell therapy market

The stem cell therapy market is segmented into North America, Europe, Asia Pacific, RoW. The stem cell therapy market in the Asia Pacific region is expected to grow at the highest CAGR during the forecast period.

Factors such as the growing adoption of stem cell-based treatment in the region and the growing approval & commercialization of stem cell-based products for degenerative disorders drive the growth of the stem cell therapy market in the region.

Market Dynamics

Drivers

Restraints

Opportunities

Challenges

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/qiagh1

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Stem Cell Therapy Market by Type, Therapeutic Application and Cell Source - Global Forecasts to 2026 - ResearchAndMarkets.com - Business Wire

Bone Marrow Stem Cells Comments Off on Stem Cell Therapy Market by Type, Therapeutic Application and Cell Source – Global Forecasts to 2026 – ResearchAndMarkets.com – Business Wire | May 15th, 2021