Fred Hutch science and research highlights 2019 – Fred Hutch News Service

By daniellenierenberg

Fred Hutchinson Cancer Research Center researchers continued to explore the edge of human knowledge as they seek cures for cancer, HIV and other diseases. Here we highlight a sampling of the most interesting and important research from the past year.

Why does a common virus plague bone marrow transplant patients? New study challenges dogma, opens door to new therapies.

You may not have heard of cytomegalovirus, but the two of you have likely met.

In fact, odds are its dozing inside you right now.

Cytomegalovirus, or CMV, infects at least half of all adults worldwide. Most are unaware theyre infected because their healthy immune system keeps it in check. The virus slips into dormancy, becoming a passive and lifelong passenger.

But CMV can roar back to life in anyone with a compromised immune system. The results can be life-threatening, and the virus has plagued bone marrow transplant patients for decades.

Astudy in Sciencemay rewrite the story of why the virus wreaks such havoc and hint at how to stop it.

The research challenges long-held theories about how the body controls CMV. The twist: The immune systems defense against CMV isnt a solo performance. After years of studying a mouse model, a team of researchers led byDr. Geoffrey Hillshows that an unsung actor antibodies plays a vital role.

Antibodies are one of the bodys chief ways of defending itself against infection. These Y-shaped proteins can bind, like a lock and key, to bad actors and neutralize them.

Hills insight could pave the way for cheaper, safer therapies using antibodies to protect transplant patients against CMV. In a tantalizing hint, the researchers found that a dose of the right antibodies after transplantation can keep the virus dormant in mice, without the need for any other immune cells.

This is a big deal for the transplant field, said Hill, the studys senior author and director of Hematopoietic Stem Cell Transplantation at Fred Hutch. Were turning dogma on its head, and that could meet the urgent need for inexpensive and nontoxic therapies to improve patient outcomes.

Microbiome triggers top killer after bone marrow transplant and theres a potential way to stop it

Bone marrow transplants have beencuring some blood cancers for decades. But for just as long, a potentially fatal complication has lurked in the background.

In a bone marrow transplant, a patients diseased blood-forming stem cells are wiped out and then replaced by a donors healthy cells. Those donor cells are the key to the cure; they recognize and attack the patients cancer cells.

But sometimes they attack the patients healthy cells, too. This condition, called graft-vs.-host disease, can develop throughout the patients body in organs like the skin, liver, eyes and lungs.

If GVHD occurs in the gut, it can be lethal. Buthowthe disease occurs has been a mystery.

Until now.A studypublished in the journal Immunity identifies the complex chain of events that triggers GVHD in the gut. It involves a large cast of cells and molecules, including some from a surprising source: the trillions of tiny organisms that live in and on us known as the microbiome.

The scientists, led by Drs. Motoko Koyama andGeoffrey Hillof Fred Hutch, also found a promising clue as they traced the diseases complicated pathway. One of the key players in that pathway is a chemical signal called interleukin-12. By snuffing out that signal, the researchers could prevent the disease from happening in mice. They are now applying for funding to test this approach in transplant patients via a clinical trial.

For Hill and Koyama, the study caps years of experiments trying to solve this whodunit. The question was never just academic. Both have seen transplant patients suffer and die from GVHD.

Whether you live or die after a [donor] bone marrow transplant can, to a large extent, depend on whether or not you get graft-vs.-host disease of the gut, Hill said. Now that we understand that the gut both initiates and is itself the target of GVHD, we might be able to intervene to stop the whole process from starting.

High-tech approach solves real mystery in many cancers

Genetic mutations are the spark and fuel for cancer. Hundreds of DNA mutations have been linked to human cancers, and theyre easier than ever to find and catalog, thanks to new genomic technologies.

But its remained difficult to find out what those mutations are doing to drive cancer growth so that scientists can design new treatments to intervene.

In research published in the journal Nature, a coast-to-coast group of collaborators applied a powerful new method to do just that. The team showed how one commonly mutated gene actually drives cancer growth and how, potentially, to counteract it.

Even for very well-studied mutations, its frequently not obvious what the specific underlying processes are that promote cancer growth, said the studys co-leader, Dr. Robert Bradley of Fred Hutch. When we understand how to map a mutation to the development of cancer, then we can start to think about how to block that process for therapy.

The gene Bradley and collaborators studied, called SF3B1, was mutated in 19 different ways in the several different cancer types they looked at. That gene is so critical to a fundamental cell process that when it is mutated, things get screwed up all over the cell.

The biggest surprise to the scientists was that, out of all this complexity, an elegantly simple answer emerged. No matter how SF3B1 was mutated, no matter in what type of cancer they examined, no matter what else was out of whack in the cells, just one key process was central in driving cancer growth.

Once they knew what the problematic mechanism was, the scientists could intervene. In mice, implanted human tumors started to shrink when injected with the researchers custom-designed molecular repair kit.

The experimental treatment they designed is years away from human patients. For now, they hope their work prompts other researchers to study this mechanism to prove that its happening in many cancers with SF3B1 mutations.

Study reveals how blood vessels in the bone marrow protect dormant tumor cells, suggests a way to kill them in their sleep

Researchers at Fred Hutch may have found a way to essentially smother cancer cells in their sleep, preventing them from ever waking up and forming deadly metastatic tumors.

The work, led by translational researcher Dr. Cyrus Ghajar, has also turned on its ear the longstanding belief that chemotherapy cant kill dormant disseminated tumor cells cancer cells that escape early on and hide out in other regions of the body because those cells are in a sleeper state. Theyve stopped growing, so chemo which blindly targets all fast-growing cells, healthy and otherwise doesnt work.

Thats not quite the case.

Its always been assumed that dormant cells cannot be killed by any kind of chemotherapy because theyre not dividing, said Ghajar, who runs the Laboratory for the Study of Metastatic Microenvironments at Fred Hutch. But what were showing is thats not true. Theyre relying on survival signaling in their microenvironment, in this case specifically from blood vessels within the bone marrow. And if you can take away that signaling, you can sensitize them to chemotherapy.

Ghajars paper, published in Nature Cell Biology, is the culmination of more than four years work and proposes both a paradigm shift in how we view dormant disseminated tumor cells and a new therapy to potentially slay this sleeping giant. Although its still early days, Ghajar and his team slashed the metastatic relapse rate in his mice by more than two-thirds.

Cancer doesnt just spread because a primary tumor has reached a certain size or stage. Disseminated tumor cells, or DTCs, can break off before a tumor has even formed and travel to distant sites in the body where they lie dormant until something wakes them up and they start the deadly process of metastasis, or cancer spread/colonization.

One common hideout for these sleepy creeps is the bone marrow. Dormant tumor cells have been found in the bone marrow of breast cancer patients at the very earliest stage of the disease DCIS or stage 0 and Ghajar said theyre mostly likely present in other patients with early-stage disease, as well.

Past research has shown an association between DTCs in the bone marrow of cancer patients and metastatic recurrence and not necessarily just bone metastasis.

Additional recommended articles:

Failed Alzheimers drug boosts CAR T-cell therapy

Engineered immune cells get a helping hand in new clinical trial for multiple myeloma patients

They may not have made a dent against Alzheimers. But it turns out experimental drugs called gamma secretase inhibitors, or GSIs, sure can bedevil cancer. Fred Hutch research describes how GSIs can reverse a crafty disappearing act that multiple myeloma pulls on the immune system. That ability to vanish even tricks T cells that are genetically programmed to home in on and attack myeloma cells.

* * *

How to boost cancer clinical trial participation

New study suggests loosening strict comorbidity criteria would open trials to thousands of previously exempt patients

A new study led by Dr. Joseph Unger offers a tantalizing solution to low clinical trial participation: loosen up the strict eligibility criteria. Low participation is a problem thats plagued cancer researchers for decades, with most estimates putting adult cancer patient involvement at less than 5%. In many cases, the patients clinical status that is, their various medical conditions exclude them from even being considered for a trial.

* * *

Baiting for B cells: A clever new way to make an AIDS vaccine

Researchers fish for rare blood cells that can evolve into HIV blockers

Scientists at Fred Hutch have developed a new strategy to counter the frustrating ability of HIV to sidestep vaccines designed to block it. It is a scheme that relies on one of the oldest tricks in the book for a fisherman: Use the right bait. The vaccine researchers were able to use a tiny chunk of protein as bait to fish for extremely rare white blood cells hidden within ordinary blood.

* * *

Special delivery: Gold nanoparticles ship CRISPR cargo

Scientists used their new golden courier to edit genes tied to HIV, genetic blood disorders

Tiny golden delivery trucks created at Fred Hutch can ship CRISPR into human blood stem cells, offering a potential way to treat diseases like HIV and sickle cell anemia. And the researchers behind those trucks have even bigger distribution dreams.

* * *

Immunotherapy prevents relapse in small leukemia trial

Engineered T cells kept leukemia from returning in 12 high-risk patients

The statistics are grim: For patients with high-risk acute myeloid leukemia, more than 60% will relapse within two years of a bone marrow transplant. The return of their cancer is the leading cause of death for these patients.

Butresults from a small trialof genetically modified immune cells hint at a way of protecting these patients. Scientists used engineered T cells to prevent relapse in 12 AML patients after a bone marrow transplant put their disease in remission. They all remain cancer-free after a median follow-up of more than three years.

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Nanotech turns pro-tumor immune cells into cancer-killing triple agents

Strategy doubles survival in mice with cancer

Our immune cells usually do a great job of keeping us healthy, staving off infection and killing tumor cells. But sometimes, they betray us and join the enemy: cancer. Tumors often release factors that convince immune cells to help tumors instead of hurting them. But what if these double agent immune cells could be convinced to switch allegiance yet again? Nanotechnology could be the key to redirecting specialized immune cells to attack and shrink tumors. Research showed in mice that minuscule, dissolving polymer particles can ferry genetic instructions that temporarily rewire certain immune-suppressing cells into cancer fighters without causing bodywide toxicities.

* * *

Public health throws shade on tanning, and it works

New study shows sharp drop in melanoma rates in people under 30, but skin cancer rates still going up in those over 40

In a big win for cancer prevention, Fred Hutch and University of Washington researchers found a sustained, statistically and clinically significant downtrend in melanoma rates in people under 30 a near 25% drop over 10 years time.

Fred Hutch News Service writers Susan Keown, Daine Mapes, Jake Siegel, Sabrina Richards and Sabin Russell contributed reporting for these articles.

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Fred Hutch science and research highlights 2019 - Fred Hutch News Service

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