REHOVOT, Israel & WILMINGTON, Del., July 06, 2021 (GLOBE NEWSWIRE) -- Ayala Pharmaceuticals, Inc. (NASDAQ: AYLA), a clinical-stage oncology company focused on developing and commercializing small molecule therapeutics for patients suffering from rare and aggressive cancers, today announced that Roni Mamluk, Ph.D., Chief Executive Officer of Ayala, will present at the Ladenburg Thalmann Healthcare Conference on Tuesday, July 13, 2021 at 9:00 am ET.

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Hamilton, Bermuda, July 6, 2021 – Auris Medical Holding Ltd. (NASDAQ: EARS), a company dedicated to addressing unmet medical needs through RNA therapeutics, allergy and viral infection protection, and inner ear therapeutics, today announced the selection of mutant KRAS-driven colorectal cancer as the first therapeutic indication for its OligoPhore™ oligonucleotide delivery platform. The Company intends to develop the treatment under project code AM-401 with submission of an IND targeted for the end of 2022.

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Auris Medical to Develop KRAS-Targeting RNA Treatment for Colorectal Cancer as First Therapeutic Indication for OligoPhore™ Technology

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NEW YORK, NY, July 06, 2021 (GLOBE NEWSWIRE) -- via NewMediaWire -- Tauriga Sciences, Inc. (OTCQB: TAUG) (“Tauriga” or the “Company”), a New York-based diversified Life Sciences Company, today announced that its Brand Registry Application for its flagship Tauri-Gum™ brand has been approved by Amazon Inc. (“Amazon”).  Amazon Brand Registry helps the Company protect its registered Trademarks and create a trusted experience for customers. Additionally, Amazon provides a suite of tools that enable rich text images on the Amazon detail page – which helps a business drive customer conversion and increased traffic & sales.

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DURHAM, N.C., July 06, 2021 (GLOBE NEWSWIRE) -- CoImmune, Inc., a clinical stage immuno-oncology company that will redefine cancer treatment using best-in-class yet more affordable cellular immunotherapies, today announced the appointments of Michael Fekete and Greg Tibbitts, to the Company’s board of directors. Mr. Fekete and Mr. Tibbitts bring with them a wealth of financial, capital markets and strategic expertise, and prior board level experience.

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CoImmune, Inc. Appoints Michael Fekete and Greg Tibbitts to its Board of Directors

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Saint-Herblain (France), July 6, 2021 – Valneva SE (Nasdaq: VALN; Euronext Paris: VLA), a specialty vaccine company focused on the development and commercialization of prophylactic vaccines for infectious diseases with significant unmet medical need, announced today it has appointed Vincent Dequenne as Senior Vice President Operations and Joshua Drumm as Vice President Investor Relations.

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Valneva Strengthens Management Team; Appoints Vincent Dequenne as SVP Operations and Joshua Drumm as VP Investor Relations

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Monthly information related to total number of voting rights and shares composing the share capital – June 30, 2021

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Accelus to Offer Procedure-Enabling Technology with the Goal of Making Minimally Invasive Surgery (MIS) the Standard of Care in Spine Accelus to Offer Procedure-Enabling Technology with the Goal of Making Minimally Invasive Surgery (MIS) the Standard of Care in Spine

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Integrity Implants and Fusion Robotics Merge to Form Accelus

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Company Announcement

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Capital Increase in Genmab as a Result of Employee Warrant Exercise

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OCALA, Fla., July 06, 2021 (GLOBE NEWSWIRE) -- AIM ImmunoTech Inc. (NYSE American: AIM) today announced that it will host an investor update webcast at 11:00 a.m. Eastern Time on Wednesday, July 14, 2021, to discuss recent accomplishments and upcoming milestones. Investors and other interested parties are invited to submit questions to management prior to the call's start via email to aim@crescendo-ir.com.

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AIM ImmunoTech to Host Investor Update Webcast on Wednesday, July 14th at 11:00 AM ET

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SAN DIEGO, July 06, 2021 (GLOBE NEWSWIRE) -- Sorrento Therapeutics, Inc. (NASDAQ: SRNE, "Sorrento") announced today that the company has received FDA clearance to proceed with a Phase 2 clinical study of RTX for treating moderate-to-severe osteoarthritis of the knee pain (OAK).

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FDA Clears Sorrento Phase 2 Trial Of Non-Opioid Product Candidate Resiniferatoxin (RTX) For Treatment of the Knee Pain in Osteoarthritis (OA) Patients

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SANTA MONICA, Calif., July 06, 2021 (GLOBE NEWSWIRE) -- Opiant Pharmaceuticals, Inc. (“Opiant”) (NASDAQ: OPNT) today announced positive top-line results from its confirmatory pharmacokinetic (“PK”) study for OPNT003, nasal nalmefene, for opioid overdose.

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Opiant Pharmaceuticals Announces Positive Top-line Results of Confirmatory Pharmacokinetic (PK) Study for OPNT003, Nasal Nalmefene, a Novel...

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BELTSVILLE, Md., July 06, 2021 (GLOBE NEWSWIRE) -- NextCure, Inc. (Nasdaq: NXTC), a clinical-stage biopharmaceutical company discovering and developing novel, first-in-class immunomedicines to treat cancer and other immune-related diseases, today announced the initiation of a Phase 1/2 clinical trial for NC762, a humanized B7-H4 monoclonal antibody.

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NextCure Initiates Phase 1/2 Clinical Trial of NC762 for Solid Tumors

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TORONTO, July 06, 2021 (GLOBE NEWSWIRE) -- Auxly Cannabis Group Inc. (TSX - XLY) (OTCQX: CBWTF) ("Auxly" or the "Company") a leading consumer packaged goods company in the cannabis products market, is pleased to announce the implementation of amendments to certain provisions of its previously issued $123 million debenture (the “Debenture”) and investor rights agreement (the “Investor Rights Agreement”) dated September 25, 2019 (collectively, the “Amendments”) with its strategic partner, Imperial Brands PLC (“Imperial Brands”), pursuant to the terms of the previously announced amending agreement dated April 19, 2021.

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Auxly Strengthens Financial Position With the Implementation of Amendments to Imperial Brands $123 Million Convertible Debenture and Sale of Curative...

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Data Readout for First Four Treatment Arms Expected in the Fourth Quarter of 2021 Data Readout for First Four Treatment Arms Expected in the Fourth Quarter of 2021

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Eloxx Pharmaceuticals Provides Enrollment Update for Ongoing Phase 2 Clinical Studies for Cystic Fibrosis

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– Dr. Sorensen to become CEO of a start-up hemostasis and thrombosis company – – Dr. Sorensen to become CEO of a start-up hemostasis and thrombosis company –

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Codiak BioSciences Announces the Transition of Benny Sorensen, M.D., Ph.D. to Scientific Advisory Board Member and Clinical Consultant Roles

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AUSTIN, Texas, July 06, 2021 (GLOBE NEWSWIRE) -- XBiotech Inc.’s (NASDAQ: XBIT) (“XBiotech”) Board of Directors has declared an extraordinary cash dividend of approximately $2.50 per share, or up to an aggregate of $75 million, to holders of its common stock. This one-time, special dividend will be payable on July 23, 2021 to stockholders of record at the close of business on July 16, 2021.

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XBiotech Announces Dividend to Holders of Common Stock

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Geneva, Switzerland, July 7, 2021 - Addex Therapeutics (SIX:ADXN), a clinical-stage pharmaceutical company pioneering allosteric modulation-based drug discovery and development, announced today that Chief Executive Officer, Tim Dyer, will present at Access to Giving Virtual Conference at 9 AM ET on July 14, 2021. Mr. Dyer will give a corporate update, including an overview of recent advances in Addex’s clinical trial program. The conference is free to all registrants.

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Addex Therapeutics to Present at Access to Giving Virtual Conference on July 14, 2021

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The first paper, titled PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress, takes a look at the effect of inflammation on the transcription factor PU.1 and its effect on the production of hematopoietic stem cells (HSCs), or the immature cells found in the bone marrow that can turn into blood cells, according to the study author James Chavez, BS.

Second corresponding author Eric Pietras, PhD, CU Cancer Center Member, said the research from Chavez challenged his previous understanding of how inflammation impacts HSCs.

We thought that introducing a proinflammatory cytokine like Interleukin (IL)-1 would make hematopoietic stem cells proliferate, because when you have inflammation, the body typically interprets it as a signal to produce more white blood cells to fight off an infection or injury, Pietras said, in a CU interview.

However, he and his team discovered that in the presence of IL-1, genes that control the creation of additional hematopoietic stem cells were turned off rather than on, specifically genes related to the synthesis of proteins, were the key of building new cells. I think some of the best science is that which disproves your own notions and dogmas, Pietras said in the CU interview.

The team ended up finding a transcription factor called PU.1 that represses protein synthesis genes in HSCs during periods of inflammation.

That made us wonder what would happen if we got rid of PU.1, Pietras said in the CU interview. He and his team used genetic mouse models that reduced the amount of PU.1 in the HSCs or remove it altogether, uncovering that when PU.1 is reduced or removed, inflammation caused by the introduction of IL-1 triggers the proliferation and expansion of HSCs.

Our findings point to an interesting mechanism for how inflammation can trigger differences in cell fitness when normal HSCs have to compete with HSCs harboring oncogenic mutations that are known to disable or reduce PU.1, Pietras said in the CU interview. In this case, those PU.1- deficient HSCs act like normal cells as long as there's no inflammation. But as soon as you trigger an inflammatory response, it's like throwing gasoline on a fire. The HSCs with loss of PU.1 expand because there is no longer a mechanism to turn their protein synthesis off. And when that happens, you get uncontrolled growth of the PU.1-deficient hematopoietic stem cells, which can eventually lead to leukemia, a type of blood cancer.

The second paper, titled Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors, co-led by DeGregori and Pietras, looks at the impact of the proinflammatory cytokine IL-1 on hematopoietic stem and progenitor cells (HSPCs).

One of the primary goals, according to DeGregori, was to better understand the factors that determine what kind of mature blood cells are produced from our blood stem cells, or the HSPCs, in response to chronic inflammation. Mouse models were studied by injecting with IL-1 to copy an infection and cause inflammation. This action impacted blood cell production towards making granulocytes, which is a type of white blood cell that helps the immune system fight infections, according to the study authors.

The team also found that inflammation seemed to alter selection in the HSPCs toward oncogenic mutations of the Cebpa gene that are often found in leukemia.

"Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, DeGregori said in the CU interview. For every good process that happens in your body, such as fighting infection, there can also be adverse reactions that create risk. And we think inflammation creates some level of risk, particularly if it's a chronic situation.

DeGregori added that the most widespread cause of inflammation is old age, and examples of conditions that could cause long-term inflammation include arthritis and chronic infections, such as colitis.

"When we get old, many of us become chronically inflamed, DeGregori said in the CU interview. Not everyone experiences the same level of inflammation, but higher inflammation tends to coincide with worse outcomes for people. Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, particularly acute myeloid leukemia (AML).

DeGregori and Pietras note that solving this issue is more complicated than wiping out inflammation altogether.

Inflammation is critically important for surviving infections, DeGregori said in the CU interview. Over evolutionary time, dying from infection was a major risk, so we evolved inflammation as a mechanism to avoid that. On the other hand, we've shown that chronic inflammation could promote selection for oncogenic events, such as through inhibition of Cebpa.

According to Pietras, the next step is to apply these findings to human biology.

I think there are a few different implications for the work, Pietras said in the CU interview. One is that we're learning more about when and where stem cells first gain mutations and the extent to which inflammation can impact the capacity of these mutant HSCs to eventually initiate leukemia. What this tells us is that if we can intervene at an early stage, we may be able to reduce the risk of getting blood cancer.

The studies helped to show that both preventive measures for those at higher risk of developing cancer and treatments for those who are already diagnosed could potentially be improved by addressing bad inflammation while maintaining the immune systems ability to function, according to study authors.

"We don't want to limit someone's risk of getting leukemia and at the same time increase their risk of dying from an infection, DeGregori said in the CU interview. But the more we learn about it, the better we might get at finding that happy balance.

REFERENCE

Gleaton V. Two Studies by CU Cancer Center Researchers Explore Link Between Inflammation and Leukemia. University of Colorado Cancer Center. Published June 28, 2021. Accessed July 1, 2021. https://news.cuanschutz.edu/cancer-center/two-studies-inflammation-and-leukemia

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Chronic Inflammation Can Serve as A Key Factor in The Development of Leukemia, Other Blood Cancers - Pharmacy Times

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Our cells have abilities that go far beyond the fastest, smartest computer. They generate mechanical forces to propel themselves around the body and sense their local surroundings through a myriad of channels, constantly recalibrating their actions.

The idea of using cells as medicine emerged with bone marrow transplants, and then CAR-T therapy for blood cancers. Now, scientists are beginning to engineer much more complex living therapeutics by tapping into the innate capabilities of living cells to treat a growing list of diseases.

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That includes solid tumors like cancers of the brain, breast, lung, or prostate, and also inflammatory diseases like diabetes, Crohns, and multiple sclerosis. One day, this work may extend to regenerating tissues outside or even inside the body.

Taking a page from computer engineers, biologists are trying their hands at programming cells by building DNA circuits to guide their protein-making machinery and behavior.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload, said Hana El-Samad, PhD, a professor of biochemistry and biophysics. Maybe they kill a little bit and then deliver a therapeutic payload that cleans up. And the next program over encourages the rejuvenation of healthy cells.

These engineered cell therapies would be a huge leap from traditional therapies, like small molecules and biologics, which can only be controlled through dose, or combination, or by knowing the time it takes for the body to get rid of it.

If you put in drugs, you can block things and push things one way or the other, but you can't read and monitor whats going on, said Wendell Lim, PhD, a professor of cellular and molecular pharmacology who directs the Cell Design Institute at UCSF. A living cell can get into the disease ecosystem and sense what's going on, and then actually try to restore that ecosystem.

Like people, cells live in communities and share duties. They even take on new identities when the need arises, operating through unseen forces that biologists term, self-organizing.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload.

Hana El-Samad, PhD

Some living cell therapies could be controlled even after they enter the body.

Lim and others say it is possible to begin adapting cells into therapy, even when so much has yet to be learned about human biology, because cells already know so much.

Their built-in power includes dormant embryonic abilities, so a genetic nudge in the right place could enable a cell to assume a new function, even something it has never done before.

When a cell, a building block thats 10 microns in diameter can do that, and you have 10 trillion of them in your body, its a whole new ballgame, said Zev Gartner, PhD, a professor of pharmaceutical chemistry who studies how tissues form. Were not talking about engineering in the same way that somebody working at Ford or Intel or Apple or anywhere else thinks about engineering. Its a whole new way of thinking about engineering and construction.

For several years now, synthetic biologists have been building rudimentary feedback circuits in model organisms like yeast by inserting engineered DNA programs. Recently, Lim and El-Samad put these circuits into mice to see if they could tamp down the excess inflammation from traumatic brain injury.

They demonstrated that engineered T-cells could get into the sites of injury in the brain and perform an immune-modulating function. But its just a prototype of what synthetic circuits could do.

You can imagine all kinds of scenarios of therapies that dont cause any side effects, and do not have any collateral damage, said El-Samad.

UCSF researchers are building ever more complex circuits to move cells around the body and sense their surroundings. They hope to load them with DNA programs that trigger the cells protein-making machinery to do things like remove cancerous cells, then repair the damage caused by the tumors haphazard growth.

Or they could make cells that send signals to finetune the immune system when it overreacts to a threat or mistakenly attacks healthy cells. Or build new tissue and organs from our bodys own cells to repair damage associated with trauma, disease, or aging.

The fact that biological systems and cellular systems can self-organize is a huge part of biology, and thats something were starting to program, Lim said. Then we can make cells that do the functions that we want. We aspire to not only have immune cells be better at killing and detecting cancer but also to suppress the immune system for autoimmunity and inflammation or go to the brain to fight degeneration.

These UCSF scientists are on their way to engineering cell-based solutions to different diseases.

Tejal Desai, PhD, a professor and chair of the Department of Bioengineering and Therapeutic Sciences, is employing nanotechnology to create tiny depots where cells that have been engineered to treat Type 1 diabetes or cancer can refuel with oxygen and nutrients.

Having growth factors or other factors that keep them chugging along is very helpful, she said. Certain cytokines help specific immune cells proliferate in the body. We can design synthetic particles that present cytokines and have a signal that says, Come over to me. Basically, a homing signal.

Ophir Klein, MD, PhD, a professor of orofacial sciences and pediatrics, employs stem cell biology to research treatments for birth defects and conditions like inflammatory bowel disease. He is working with Lim and Gartner to create circuits that induce cells to grow in new ways, for example to repair the damage to intestines in Crohns disease.

Cells and tissues are able to do things that historically we thought they were incapable of doing, Klein said. We dont assume that the way things happen or dont happen is the best way that they can happen, and were trying to figure out if there are even better ways.

Faranak Fattahi, PhD, a Sandler Faculty Fellow, is developing cell replacement therapy for damaged or missing enteric neurons, which regulate the muscles that move food through the GI tract. She generated these gut neurons using iPS cell technology.

What we want to do in the lab is see if we can figure out how these nerves are misbehaving and reverse it before transplanting them inside the tissue, she said. Now, she is working with Lim to refine the cells, so they integrate into tissues more efficiently without being killed off by the immune system and work better in reversing the disease.

Matthias Hebrok, PhD, a professor in the Diabetes Center, has created pancreatic islets, a complex cellular ecosystem containing insulin-producing beta cells, glucagon-producing alpha cells and delta cells.

Now, he is working on how to make islet transplants that dont trigger the immune system, so diabetes patients can receive them without immune-suppressing drugs.

We might be able to generate stem-cell derived organs that the recipients immune system will either recognize as self or not react to in a way that would disrupt their function.

In health, the community of cells in these islets perform the everyday miracle of keeping your blood sugar on an even keel, regardless of what you ate or drank, or how little or how much you exercised or slept.

To me, at least, thats the most remarkable thing about our cells, Gartner said. All of this stuff just happens on its own.

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Beyond CAR-T: New Frontiers in Living Cell Therapies - UCSF News Services

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Background

Lymphoid non-T cells that can kill virally infected and tumor cells were described more than four decades ago and termed natural killer (NK) cells.1 NK cells can attack tumor cells without priming and their activity depends on a range of stimulatory and inhibitory receptors.2,3 NK cells comprise about 515% of the human peripheral blood mononuclear cells (PBMCs) and are part of the native immune system that screen cell membranes of autologous cells for a reduced expression of MHC class I molecules and increased expression of cell stress markers.4,5 NK cells mediate the direct and rapid killing of freshly isolated human cancer cells from hematopoietic and solid tumors.6,7 (Figure 1) NK cells in human peripheral blood, bone marrow and various tissues are characterized by the absence of T cell receptors (TCR) and the corresponding CD3 molecules as well as by the expression of neural cell adhesion molecule (NCAM/CD56).8 Human NK cells are generated from multilineage CD34+ hematopoietic progenitors in the bone marrow and their maturation occurs at this site of origin as well as in the lymphoid organs but not in thymus.9 In blood, NK cells show a turnover time of approximately 2 weeks with a doubling within 13.5 days in vivo and in vitro cytokine stimulation of peripheral blood NK cells can result in expansion with a median of 16 (range 1130) population doublings.10

Figure 1 NK cells and other immune cells in the tumor microenvironment. NK cells of the CD56dim CD16+ phenotype secrete interferon- (IFN-), which increases the expression of MHC class I of tumor cells, enhancing the presentation of tumor antigens to T cells. Inhibitory checkpoint molecules expressed by NK cells can be blocked using specific monoclonal antibodies (ICIs). NK cells of the CD56bright CD16- phenotype recruit dendritic cells (DCs) to the tumor microenvironment (TME) and drive their maturation via chemokine ligands CCL5, XCL1 and FMS-related tyrosine kinase 3 ligand (FLT3L). DCs in turn stimulate NK and T cells via membrane-bound IL-15 (mbIL-15) and 41BBL secretion. Eventually, NK cells lyse tumor cells resulting in release of cancer antigens, which are then presented by DCs, to provoke specific T cell activation in relation with MHC class I molecules. The immunotherapeutic effect of NK cells includes the removal of immunosuppressive MDSCs.

NK cells are not only present in peripheral blood, lymph nodes, spleen, and bone marrow but they can also migrate to sites of inflammation in response to distinct chemoattractants. The majority of CD56dim subpopulation of the whole NK cells in peripheral blood (approximately 90%) exhibits high expression of the Fc receptor FcRIII (CD16), killer cell immunoglobulin-like receptors (KIRs) and perforin-mediated cytotoxicity whereas a minor population of CD56bright CD16- KIR- CD94/NKG2A+ (approximately 515%) of NK cells is primarily producing cytokines, including IFN- and TNF-1113 These two NK cell populations have been termed conventional NK cells in contrast to distinct tissue-resident NK cell populations localizing to liver, lymphoid tissue, bone, lung, kidney, gut and uterine tissue as well as distinct adaptive NK cell populations.14 However, CD56 and CD16 are not specific for NK cells and, furthermore, the heterogeneous tissue-resident populations show expression of adhesion molecules and CD69 and may represent an immature NK cell type. Adaptive NK cells are observed in connection with viral infections and exhibit memory cell-like properties. Overall, a wide diversity of receptor expressions of NK cells has been observed and, so far, the function of many of these subpopulations has not been fully characterized.

NK cells can eliminate target cells controlled by signals derived from activating (eg, NCRs or NKG2D) and inhibitory receptors (eg, KIRS or NKG2A).1517 Normal host cells are protected from NK cells attacks through inhibitory KIRs, that identify the self-MHC class I molecules.15 In particular, the germline-encoded NK receptors include the activating receptors NKG2D, DNAM-1, the natural killing receptors NKp30, NKp44, NKp46, and NKp80, the SLAM-family (Signaling Lymphocyte Activating Molecule) receptors for the elimination of hematopoietic tumor cells and the inhibitory KIRs.18 The activating signaling molecules promote tumor cell killing, cytokine production, immune cell activation, and proliferation and the NKpXX receptors, when engaged, all trigger alterations of the cellular calcium flux and NK cell-mediated killing and secretion of IFN- (Figure 1).

The interaction between KIRs and self-MHC molecules governs the maturation of NK cell, a process termed licensing.11,19,20 As alternative of MHC downregulation, cancer cells may be recognized by the overexpression of binding molecules for activating NK cell receptors. Ligands for the activating NKG2D receptor, such as MHC class I polypeptide-related sequence A (MICA), MICB and others are presented by cancer cells preferentially in response to cellular stress.21 A separate mechanism known as antibody-dependent cell cytotoxicity (ADCC) results in elimination of antibody-coated cell via the CD16 FcRIII receptor.22

NK cell-mediated lysis of target cells is mainly achieved through the release of the cytotoxic effector perforin and granzymes A and B but NK cells also produce a range of cytokines, both proinflammatory and immunosuppressive, such as IFN-, TNF- and IL10, respectively, as well as growth factors such as granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and IL-3 (Figure 1). CD56dim NK cells can produce very rapidly IFN- within 2 to 4 hours after triggering through NKp46 and NKp30 activating receptors (ARs).12,13 NK cellderived cytokine production impacts dendritic cells, macrophages and neutrophils and empower NK cells to regulate subsequent antigen-specific T and B cell responses. Activated NK cells lose CD16 (FcRIII) and CD62 ligand through the disintegrin and metalloprotease 17 (ADAM17), and inhibition of this protease enhances CD16-mediated NK cell function. Cytokine stimulation also downregulates CD16 and upregulates CD56 expression. Moreover, certain cytokines can greatly enhance the cytotoxicity and cytokine production of the CD162 CD56bright and CD161 CD56dim NK cell subsets, respectively.23,24

In cancer patients, NK cells target cells low/deficient of MHC-class I or bearing altered-self stress-inducible proteins.17,25 Besides tumor cell killing through release of perforin and granzyme and secretion of immunoregulatory mediators such as nitric oxide (NO) effects cell death mediated by TNF-family members such as Fas-L or TRAIL. The degree of tumor infiltration of NK cells seems to have prognostic value in gastric carcinoma, colorectal carcinoma and lung carcinomas, thus indicating a protective role of the NK cell infiltrate.26,27 NK cell infiltration of tumors depends on their expression of heparinase.28 NK cells may further attract T cells to the tumor region and elevate inflammatory responses through secretion of cytokines and chemokines.29 Furthermore, NK cells have been suggested to suppress metastasis through elimination of circulating tumor cells (CTCs).30

NK cells seem well suited for anticancer immunotherapy and cells for clinical administration can be isolated from peripheral or umbilical cord blood. Peripheral blood NK cells are prepared by leukapheresis and further enriched by density gradient centrifugation (Figure 2). Subsequently, the combination of T cell depletion with CD56 cell enrichment yields highly purified NK cell populations.31 NK cells gained from peripheral blood of healthy persons are typically in a resting state and can be activated by exposure to IL-2. However, supplementation with IL-2 and infusion to cancer patients has resulted in severe side effects, such as vascular leak syndrome and liver toxicity.32 Studies with native autologous NK cells have yielded disappointing results. The most efficient NK cell expansion was observed with K562 NK target cells co-expressing membrane-bound IL-15 (mbIL-15) and 41BBL.31 This technique yields enough NK to provide cells for at least four infusions at 50 million cells/per kg from one leukapheresis product observing GMP conditions.31 However, many mechanisms mediate NK cell suppression in the tumor microenvironment (TME), several of which also impair T cell responses.33,34 In case of NK cells, NKG2D ligand release can occur by shedding and these soluble ligands prevent NK cell-tumor cell interaction and the cytotoxic response.35,36

Figure 2 Isolation, activation and propagation of allogeneic NK cells. Peripheral blood mononuclear cells (PBMCs) are prepared from healthy donors by leukapheresis. PBMC depletion of CD3+ T cells, prevents GvHD after infusion and further purification is achieved by positive CD56+ cell selection. These cell preparations are infused or activated with IL-2 or a mixture of IL-12, IL-15 and IL-18. Another method for NK cell stimulation involves ex vivo coculture with the K562 cell line expressing membrane-bound IL-15 (mbIL-15) and 41BBL that is irradiated to abolish expansion. Umbilical cord blood NK cells can be used similar to peripheral blood NK cells or enriched for CD34+ hematopoietic progenitors, followed by differentiation to NK cells. NK cells can be gained from induced pluripotent stem cells (iPSCs) via successive hematopoietic and NK cell differentiation, followed by stimulation with cells expressing mbIL-21. Before infusion of allogeneic NK cells, patients receive lymphodepleting chemotherapy to facilitate temporary engraftment of the infused NK cells.

In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future.

The lungs are frequently challenged by pathogens, environmental damages and tumors and contain a large population of innate immune cells.37,38 Involvement of NK cells in lung diseases, such as cancer, chronic obstructive pulmonary disease (COPD), asthma and infections, has been amply reported.39 Chronic inflammation drives the irreversible obstruction of the lung function in COPD and local NK cells show hyperresponsiveness in COPD and kill autologous lung CD326+ epithelial cells.40 Therefore, targeting NK cells may represent a novel strategy for treating COPD. Furthermore, NK cells from cigarette smoke-exposed mice produce higher levels of IFN- upon stimulation with cytokines or toll-like receptor (TLR) ligands.41

Lung NK cells account for approximately 1020% of local lymphocytes and have migrated to the lungs from bone marrow.42 These cells exhibit the phenotype of the CD56dim CD16+ subset and are located in the parenchyma.43 Lung NK cells show major differences in phenotype and function to those from other tissues and, for example, KIR-positive NK cells and differentiated CD57+ NKG2A cells are found in higher numbers in the lungs compared to matched peripheral blood.37,38 In vivo, human lung NK cells respond poorly to activation by target cells in comparison to peripheral blood NK cells, most likely due to suppressive effects of alveolar macrophages and soluble factors in the fluid of the lower respiratory tract.44 The presence of hypofunctional NK cells seems to regulate the pulmonary homeostasis in the presence of constantly irritation by environmental and autologous antigens.

Unlike other tissues, the lung NK cell diversity and its acquisition have been very little studied, especially regarding the resident lung populations. Although the majority of lung NK cells are of a non-tissue-resident phenotype, a small CD56bright CD49a+ lung NK cell subset has been found.45 NK cell diversity occurs for the main resident population within the lung, namely CD49a+CD56bright CD16 NK cells that can be split into four different resident subpopulations according to the residency markers CD69 and CD103.47 The CD69+CD103+ subset is the most important as compared to single positive or double negative subsets. The respective significance of these subsets in terms of ontogeny, differentiation, or functionality remains to be characterized.

The CD16 NK cells in the human lung comprises a heterogeneous cell population and the CD69+CD49a+CD103 and CD69+CD49a+CD103+ tissue-resident NK cells are clearly distinct from other NK cell subsets in the lung and other tissues, whereas CD69spCD16 NK cells (lacking expression of CD49a and/or CD103) largely represent conventional CD69CD16 NK cells.47 Furthermore, lung tissue-resident NK cells are functionally competent and constitute a first line of defense in the human lung. Protein and gene expression signatures of CD16 NK cell subsets correlated with distinct patterns of expression of CD69, CD49a, and CD103 and corroborated the CD69+CD49a+CD103 and CD69+CD49a+CD103+ NK cells as tissue-resident NK cells.48 In contrast, CD69spCD16 NK cells are more similar to CD69CD16 NK cells and showed lower expression of genes associated with tissue-residency.

On the course of NK cell differentiation less differentiated NK cells are hypofunctional but respond stronger to cytokine stimulation and more differentiated NK cells exert more potent ADCC-dependent cell killing.46,49 The early activation antigen CD69 is expressed on a wide range of tissue-resident lymphocytes, including T cells and NK cells, and promotes retention of the cells in the tissue.38,50 Highly differentiated and hypofunctional CD69+ CD56dim CD161+ NK cells constitute the dominant NK cell population in the human lung. In summary, these results indicate that the human lung is mainly populated by NK cells migrating between lung and blood, rather than by CD69-positive tissue-resident cells. The mechanisms controlling this distribution of the lymphocyte populations is not known but may comprise changes in the homing of NK cells, increased apoptosis of NK cells and increased expansion or recruitment of tissue-resident T cells.

Although the incidence of lung cancer is declining, the survival rates remain poor due to a lack of early detection and only recent progress in targeted cancer therapies that are still only feasible for a limited subpopulation of patients.51,52 The host of immune cells involved in lung cancer include CD4+ and CD8+ T lymphocytes, neutrophils, monocytes, macrophages, innate lymphoid cells (ILCs), dendritic cells and NK cells. In lung cancer patients, peripheral NK cell cytotoxicity and INF- production was reported to be reduced.5356 Especially, a lower cytotoxic activity in NK cells was observed in smokers due to the suppression of the induction of IL-15 and IL-15-mediated NK cell functions in human PBMCs.57 Furthermore, the granzyme B release by NK cells from lung cancer tissue is lower compared to adjacent normal tissue.58 Additionally, peripheral NK cells of NSCLC patients are present in lower cell numbers and display a distinctive receptor expression with downregulation of NKp30, NKp80, CD16, DNAM1, KIR2DL1, and KIR2DL2, but upregulation of NKp44, NKG2A, CD69, and HLA-DR. Furthermore, low levels of IFN- and CD107a result in impaired cytotoxicity and promotion of tumor growth.54,59,60 The CD56bright CD16-NK cell subset is highly enriched in the tumor infiltrate and show activation markers, including NKp44, CD69, and HLA-DR.5961 However, the release of soluble factors by NSCLC tumor cells inhibit the activity of granzyme B and perforin and the induction of IFN- in intratumoral NK cells and suggest a local inhibition of NK cells by the NSCLC TME.62 T cell immune checkpoint molecules programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA4), lymphocyte activation gene 3 protein (LAG3) and TIM3 are expressed by subpopulations of NK cells and might reduce NK antitumor responses. In solid tumors, vascular supply may be ineffective causing hypoxia and low nutrient levels in the TME that may impair NK cell metabolism and antitumor cytotoxicity as demonstrated in lung experimental animal models.63,64 Additionally, the CD56bright CD16- NK cells enhance protumor neoangiogenesis through secretion of VEGF, placental growth factor and IL-8/CXCL8.65

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer linked to smoking that has a dismal prognosis and invariably develops resistance to chemotherapy within a short time.66 Despite a high tumor mutational burden, immune checkpoint inhibitors show minor prolongation of survival in SCLC patients.66,67 In particular, Nivolumab (anti-PD1 antibody) was approved for third-line treatment and the combination of atezolizumab (anti-PDL1 antibody) with carboplatin and etoposide was approved for first-line treatment of disseminated SCLC, resulting in minor survival gains.68,69 NK cells are critical in suppressing lung tumor growth and while low MHC expression would make SCLC resistant to adaptive immunity, this should make SCLCs susceptible to NK cell killing.64,70 In comparison to the peripheral blood NK cells of healthy individuals, the NK cells of SCLC patients are present in equal cell counts but exhibit lower cytotoxic activity, downregulation of NKp46 and perforin expression.55 Lack of effective NK surveillance seems to contribute to SCLC progress, primarily through the reduction of NK-activating ligands (NKG2DL). SCLC primary tumors possess very low levels of NKG2DL mRNA and SCLC lines largely fail to express NKG2DL at the protein level.66,71 Accordingly, restoring NKG2DL in experimental models suppressed tumor growth and metastasis in a NK cell-dependent manner. Furthermore, histone deacetylase (HDAC) inhibitors induced NKG2DL re-expression and resulted in tumor suppression by NK and T cells. Actually, SCLC and neuroblastoma are the two tumor types with lowest NKG2DL-expression. In conclusion, epigenetic silencing of NKG2DL results in a defect of NK cell activation and immune escape of SCLC and neuroblastoma. Poor immune infiltrates in SCLC tumors combined with reduced NK and T cell recognition of the tumor cells seem to contribute to immune resistance of SCLCs.72

A majority of NSCLC patients do not benefit from the current IC-directed immunotherapy. CD56dim CD16+ NK cells comprise the majority of NK cells in human lungs and express KIRs and a more differentiated phenotype compared with NK cells in the peripheral blood.38,73 However, human lung NK cells were hyporesponsive toward target cell stimulation, irrespective of priming with IFN-. NK cells are activated by MICA and MICB expressed by stressed tumor cells and are recognized by NK cell receptors NKG2D.74 Preclinical studies show that NKG2A or TIGIT blockade enhances antitumor immunity mediated by NK cells.2 However, the poor infiltration of NK cells into solid tumors, alterations in activating/inhibitory signals and adverse TME conditions decrease the NK-mediated killing. NK cells can be inactivated by different cells such as Tregs and MDSCs but also by soluble mediators such as adenosine.75,76 Adenosine represents one of the most potent immunosuppressive factors in solid tumors that is produced in the tumor stroma by degradation of extracellular ATP.7779 ATP and ADP are degraded by membrane-expressed ectonucleotidases such as CD39 and enhance the influx and the suppressive capacity of Tregs and MDSCs in solid tumors. NK cells are strongly involved in eliminating circulating tumor cells (CTCs), but their activity can be inhibited by soluble factors, such as TGF- derived from M2 macrophages.80,81 One approach uses cytokines to selectively boost both the number as well as the efficacy of anti-tumor functions of peripheral NK cells.82 The gene signature of NK cell dysfunction in human NSCLC revealed an altered migratory behavior with downregulation of the sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1).83 Additionally, the expression of the immune inhibitory molecules CTLA-4 and killer cell lectin like receptor (KLRC1) were elevated in intratumoral NK cells and CTLA-4 blockade could partially restore the impaired MHC class II expression on dendritic cell (DC). In summary, the intratumoral NK dysfunction can be attributed to direct crosstalk between tumor and NK cells, activated platelets and soluble factors, such as TGF-, prostaglandin E2, indoleamine-2,3-dioxygenase, adenosine and IL-10.19,26,54,83 In addition, a specific migratory signature could explain the exclusion of NK cells from the tumor interior. NK cells in NSCLC distribute to the intratumoral fibrous septa and to the borders between tumor cells and surrounding stroma.54,59 It has been suggested that a barrier of extracellular matrix proteins may be responsible for the restriction of NK cells primarily to the tumor stroma, such preventing direct NK celltumor cell interactions.84,85 In contradiction, ultrastructural investigations demonstrated NK cells are rather flexible and capable of extravasation and intratumoral migration.59 CD56bright CD162+ NK cells express CCR5 that is known to mediate the chemoattraction of specific leukocyte subtypes and explain their accumulation in tumor tissues.13 Infiltration of the tumors by NK cells was reported to be linked with a favorable prognosis in lung cancer.26,86 However, Platonova et al reported that NK cell infiltration lacks any correlation with clinical outcomes in NSCLC.47,54 The poor prognostic significance of NK cells in NSCLC seems to be associated with the intratumoral NK cell dysfunction in patients with intermediate or advanced-stage tumors.

It would be of great importance to target chemokine receptors on NK cells to enable them to enter tumor tissues. NK cells acquire inhibitory functions within the TME, the reversion of which will enable NK cells to activate other immune cells and exert antitumor cytotoxic functions.87 In addition, several clinical trials based on NK cell checkpoints are ongoing, targeting KIR, TIGIT, lymphocyte-activation gene 3, TIM3 and KLRC1.88 NK cell dysfunction favors tumor progress and restoring NK cell functions would represent an important potential strategy to inhibit lung cancer. These approaches include the activation of NK cells by exposing to interleukins such as IL-2, IL-12, IL-15, IL-18, the blockade of inhibitory receptors of NK cells by targeting NKG2A, KIR2DL1 and KIR2DL2 as well as the enhancement of NK cell glycolysis by inhibition of fructose-1,6-bisphosphatase 1 and altering the immunosuppressive TME by neutralization of TGF-.37,53 Pilot clinical trials of NK cell-based therapies such as administration of cytokines, NK-92 cell lines and allogenic NK cell immunotherapy showed promising outcomes on the lung cancer survival with less adverse effects. However, due to the lack of larger clinical trials, the NK cell targeting strategy has not been approved for lung cancer treatment so far.

Most of studies regarding NK cell-based immunotherapy have been performed in hematologic malignancies. However, there are increasingly data available that show that NK cells can selectively recognize and kill cancer stem cells in solid tumors.89 Furthermore, Kim et al showed the essential role of NK cells in prevention of lung metastasis.90 Additionally, Zhang et al studied the efficacy of adaptive transfer of NK and cytotoxic T-lymphocytes mixed effector cells in NSCLC patients.91 A prolonged overall survival was detectable in patients after administration of NK cell-based immunotherapy. In a trial of Lin et al, the clinical outcomes of cryosurgery combined with allogenic NK cell immunotherapy for the treatment of advanced NSCLC were improved with elevated immune functions and quality of life.92

The efficacy of NK cell-based adoptive immunotherapy was also investigated in SCLC patients. Ding et al studied the efficacy and safety of cellular immunotherapy with autologous NK, T cells and cytokine-induced killer cells as maintenance therapy for 29 SCLC patients and demonstrated an increased survival of the patients.93 Importantly, lung cancer-infiltrating NK cells can mainly function as producers of relevant cytokines, either beneficial or detrimental for the antitumor immune response, and activation can transform CD56bright CD162+ KIR2+ NK cells into CD56dim CD161+ KIR1+ NK cells with higher cytotoxic activity.94 The switch from a CD56bright phenotype to a CD56dim NK cell signature can take place in lymph nodes during inflammation and these cells circulate into peripheral blood as KIR+CD16+ NK cells with low cytotoxic ability. However, the secondary lymphoid organ (SLO) NK cells acquire cytotoxic activity upon stimulation with IL-2. Malignant NSCLC tumor areas show high presence of Tregs and minor NK cell infiltration, whereas non-malignant regions were oppositely populated, containing NK cells with marked cytotoxicity ex vivo.95 IL-2 activation of PMBCs exhibit increased cytotoxic activity against primary lung cancer cells, that is further elevated by IL-12 treatment.96 The adoptive transfer of NK cells is a therapeutic strategy currently being investigated in various cancer types. For example, Krause et al treated a NSCLC patient and 11 colorectal cancer patients with autologous transfer of NK cells activated ex vivo by a peptide derived from heat shock protein 70 (Hsp70) plus low-dose IL-2.97 The NK cell reinfusion revealed minor adverse effects and yielded promising immunological alterations.

Adaptive-like CD56dim CD16+ NK cells that were found in studies in mice and humans in peripheral blood have a distinctive phenotypic and functional profile compared to conventional NK cells.31,98 These cells have a high target cell responsiveness, as well as a longer life time and a recall potential comparable to that of memory T cells.99 Whereas adoptive NK cell transfer showed promising activities in the treatment of hematological malignancies, elimination of solid tumor cells failed due to insufficient migration and tumor infiltration.100 Furthermore, a CD49a+ KIR+ NKG2C+ CD56bright CD16 adaptive NK cell population with features of residency exists in human lung, that is distinct from adaptive-like CD56dim CD16+ peripheral blood NK cells.43 NK cells with an adaptive-like CD49a+ NK cell expansion in the lung proved to be hyperresponsive toward cancer cells. Despite their in vivo priming, the presence of adaptive-like CD49a+ NK cells in the lung did not correlate with any clinical parameters.

At the time of diagnosis, the majority (80%) of lung cancer patients present with locally advanced or metastatic disease that continues to progress despite chemotherapy.101 Lung cancer remains the leading cause of cancer death worldwide despite the responses found for immune checkpoint inhibitors (ICIs), including programmed death receptor-1 (PD1) or PD ligand 1 (PDL1)-blockade therapy.102 These ICIs has achieved marked tumor regression in some patients with advanced PD1/PDL1-positive lung cancer; however, lasting responses were limited to a 15% subpopulation of patients.103 IFN-, released by cytotoxic NK and T cells, is a critical enhancer of PDL1 expression on tumors and a predictor of response to immunotherapies.104 The high failure rate of immunotherapy seems to be a consequence of low tumor PDL1 expression and the action of further immunosuppressive mechanisms in the TME.105

NK cells expanded from induced-pluripotent stem cells (iPSCs) increased PDL1 expression of tumor cell lines, sensitized non-responding tumors from patients with lung cancer to PD1-targeted immunotherapy and killed PDL1- patient tumors (Figure 2).102 In contrast, native NK cells, that are susceptible to immunosuppression in the TME, had no effect on tumor PDL1 expression. Accordingly, only combined treatment of expanded NK cells and PD1-directed inhibitors resulted in synergistic tumor cell kill of initially non-responding patient tumors. A randomized control trial in patients with PDL1+ NSCLC found that the combination treatment of NK cells with the PD1 inhibitor pembrolizumab was well-tolerated and improved overall and progression-free survival in patients compared single agent pembrolizumab treatment.106 Importantly, during this clinical study no adverse events associated with the administration of NK cells were detected.

Early trials of autologous NK cell therapy from leukapheresis have demonstrated potency against several metastatic cancers but patients developed vascular leak syndrome due to a high level of IL-2.32,107 In contrast, other studies reported that these autologous NK cells failed to demonstrate clinical responses or efficacy at large.108,109 Adoptive transfer of ex vivo IL-2 activated NK cells showing better outcomes than the systemic administration of IL-2.107,110 The development of novel NK cell-mediated immunotherapies presumes a rich source of suitable NK cells for adoptive transfer and an enhancement of the NK cell cytotoxicity and durability in vivo. Potential sources comprise haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, permanent NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor (CAR) NK cells (Figure 2). Augmentation of the cytotoxicity and persistence of NK cells under clinical investigation is promoted by cytokine-based agents, NK cell engager molecules and ICIs.111,112 Despite some successes, most patients failed to respond to unmodified NK cell-based immunotherapy.113

Clonal NK cell lines, such as NK-92, KHYG-1 and YT cells, are an alternative source of allogeneic NK cells, and the NK-92 cell line has been extensively tested in clinical trials.114116 NK-92 cells are easily expanded with doubling times between 24 and 36 hours.115 NK-92 has received FDA approval for trials in patients with solid tumors.116 These cells are genetically unstable, which requires them to be irradiated prior to infusion. Irradiated NK-92 cells have been observed to kill tumor cells in patients with cancer, although irradiation limits the in vivo persistence of these cells to a maximum of 48 hours.117 The results are still short of a significant clinical benefit.118 An NK-92- derived product (haNK) has been engineered to express a high-affinity variant of CD16 as well as endogenous IL-2 in order to enhance effector function (Figure 2).119121 For example, Dinutuximab is a product of human-mouse chimeric mAb (ch14.18 mAb), which has demonstrated high efficacy against GD2-positive neuroblastoma cells in vitro and melanoma cells in vivo.122 In MHC-I expressing tumor cells, the effector functions of autologous NK cells are often inhibited by KIR that can be blocked with the help of anti-KIR (IPH2101).123 Stem cell-derived NK cell products from multiple sources are currently being tested clinically, including those originating from umbilical cord blood stem cells or iPSCs.124,125 NK cells account for ~515% of all lymphocytes in peripheral blood, whereas they constitute up to 30% of the lymphocytes in umbilical cord blood.126 iPSC-derived NK cells were triple gene- modified to express cleavage-resistant CD16, a chimeric antigen receptor (CAR) targeting CD19 and a membrane-bound IL-15 receptor signaling complex in order to promote their persistence.127 Thus, investigations to provide highly active modified NK cells in numbers sufficient for clinical application are actively pursued.

CAR T cells are derived from autologous T cells and genetically engineered to express an antibody single-chain variable fragment (scFv) targeting a tumor-associated antigen.128 CAR T cell therapies achieved objective response rates of >80% in patients with acute lymphocytic leukemia (ALL) and B cell non-Hodgkin lymphoma.129131 However, the drawbacks of CAR T therapy include severe adverse events such as GvHD,cytokine-release syndrome and neurological toxicities, besides inefficiencies of T cell isolation, modification and expansion as well as exorbitant costs.132 CAR NK therapy is expected to circumvent some of these problems, including the high toxicities. Primary NK cells are not ideal sources for the generation of CAR cell products, due to difficulties in cell isolation, transduction and expansion. However, NK cell expansion could be greatly improved by involvement of a K562 leukemia cell line feeder modified to express membrane-bound IL-15 (mbIL-15; Figure 2).133 Denman et al improved this method adding membrane-bound 41BBL to the K562 cell line resulting in a high expansion of NK cells within a short time.134,135 Nevertheless, current clinical trials of CAR NK cells rely mainly on processing of stem cell-derived or progenitor NK cells.136 Genetic engineering of NK cells has been performed by viral transduction or electroporation of mRNA.3 Many clinical trials of CAR NK-92 cells are ongoing, but the requirement for irradiation and resulting short persistence are limitations to the clinical efficacy of these products. NK92-CD16 cells preferentially killed tyrosine kinase inhibitor (TKI)-resistant NSCLC cells when compared with their parental NSCLC cells.137 Moreover, NK92-CD16 cell-induced cytotoxicity against TKI-resistant NSCLC cells was increased in the presence of cetuximab, an EGFR-targeting monoclonal antibody. A number of Phase I trials of CAR NK cells from various sources, including autologous peripheral blood NK cells, umbilical cord blood NK cells, NK-92 cells and iPSCs were designed to target diverse cancers, such as ALL, B cell malignancies, NSCLC, ovarian cancer or glioblastoma, and are currently active.

CAR NK cells derived from iPSCs, such as the triple-gene-modified constructions are described as a promising alternative. For example, a tri-specific killer engager (TriKE) consists of two scFvs, one targeting CD16 on NK cells and the other targeting CD33 on AML cells, linked by an IL-15 domain that promotes NK cell survival and proliferation.138 Controlled clinical trials with larger patient cohorts are required to validate these early results. Immunosuppressive factors of the TME, such as low glucose, hypoxia and MDSCs, Treg cells and tumor associated macrophages (TAMs) still suppress the antitumor functions of CAR-NK cells. Low efficiency of CAR-transduction, limited cell expansion and the scarcity of suitable targets impede the use of CAR-NK therapy despite of reports of therapeutic efficacy and safety.139

The cytokine gene transfer approaches, including interleukins and stem cell factor (SCF), have been shown to induce NK cell proliferation and increases survival capacity in vivo.140 The use of primary CAR-NK and CAR-NK lines in hematological tumors showed high specificity and cytotoxicity toward the target cells.141,142 So far, only a few clinical trial studies of CAR-NK have been registered on ClinicalTrials.gov.143 The combination of blocking ICIs on CAR-NK cells can lead to a highly efficient cancer-redirected cytotoxic activity.144,145 However, hematological cancers are responsible for only 6% of all cancer deaths and solid tumor are much more difficult to target by NK/CAR NK-based immunotherapy.146

Both the unmodified and the engineered forms of NK cell treatment are showing promise in pilot clinical trials in patients with cancer.147 This kind of immunotherapy seems to combine efficacy, safety, and relative ease of effector cell supply. The lung is populated by NK cells at a specific differentiation stage releasing cytokines but exhibiting low cytotoxicity. Poor tumor infiltration, immunosuppressive factors and cell types as well as hypoxic conditions in the TME limit the activity of NK cells. Therefore, larger numbers of activated, cytotoxic competent and armed NK cells will be required for successful therapy.

We wish to thank B. Rath for help in the preparation of the manuscript and T. Hohenheim for enduring endorsement.

The authors report no conflicts of interest in this work.

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