The immune system is our body’s defense against cancer and other threats. Recently developed drugs enable a patient’s immune system to attack cancer and potentially destroy it. These drugsthat enlist the immune system have revolutionized cancer treatment. However, despitesuccesses, not all patients respond to these exciting new drugs. Cancers that do not respond tothese drugs are known as “cold” tumors because they prevent an attack by immune cells. Thisbreakdown occurs because many cell types must communicate effectively with one another foran immune response against cancer to occur – cancer disrupts this process. We will test whetherimmune cells can be improved, such that they are resistant to the miscommunication that cancercauses. Normally, immune cells use signals to communicate with each other. Cancer eitherblocks these signals or replaces them with ones that are misleading. Our goal is to restore thesignals needed by immune cells so that they can mount an effective and sustained attack againstcancer. To realize this goal we have developed activators of these signals. We will determinewhich of these signal activators can protect immune cells from being misled or disabled bycancer. Our long-term goal is to improve cancer treatment options by developing these signalactivators into new therapies that allow a patient’s immune cells to attack a cold tumor.
Gastric cancer develops in the setting of chronic inflammation that both promotes cancer progression and that also blocks the body’s immune response which otherwise might restrain tumor growth. Chronic inflammation comprises a number of different types of white blood cells, but one type, called “myeloid derived suppressor cells”, plays an important role in blocking T lymphocytes, the main immune cell that protects us against cancer. We have shown in several mouse models that “myeloid suppressors” expand in gastric cancer and mediate some of the resistance to the newest immune therapies (called immune checkpoint inhibitors such as anti-PD1 drugs). We are proposing to study the importance of these myeloid suppressor cells further using several different mouse models and also analysis of human gastric cancer tissues. We will be testing a novel peptide shown by our lab to inhibit the expansion of myeloid suppressors, and also a small molecule that we have shown can inhibit the production of these cells in the bone marrow. Overall, our goal is to advance new therapies to target inflammatory cells that resistance to immune therapies in cancer.
While Helicobacter pylori is the major risk factor for development of stomach cancer, only 1-2% of those infected with H. pylori get gastric cancer suggesting the existence of additional necessary factors. We hypothesize the oral bacterium Fusobacterium nucleatum, which normally does not colonize the stomach, can colonized the altered tissue environment created by H. pylori infection to further drive tumor progression. Testing this hypothesis will yield new insight into the mechanisms of bacterial carcinogenesis and highlight new opportunities for intervention.
Our lab is developing treatments for human cancers by engineering immune cells called “T cells” to recognize and kill tumor cells. Engineered T cells can eradicate tumors in patients with blood cancers, like leukemia and lymphoma. However, they have had limited success so far against more common “solid tumors”, like breast and lung cancer, which are responsible for the majority of cancer deaths. Solid tumors can evade attack by inducing T cells to lose function and become “exhausted.” Strategies to preserve T cell function, thus, are needed to extend the success of engineered T cell therapy to solid tumors. Our lab has developed a mouse model of lung cancer that mimics human tumor development and patient response to therapy. In this model, T cells engineered to overexpress a gene that promotes T cell function dramatically eliminated tumors in ~50% of mice. Based partly on these results, a clinical trial is being planned to test whether these T cells are safe and effective in patients. However, our data show that tumors still progress in ~50% of mice. We will use the mouse model we developed to define why tumors progress in a subset of mice and test different combination treatments to identify regimens that improve T cell function and kill tumors most effectively. Working with Fred Hutch clinicians and industry partners, our goal is to translate the strategies that appear most effective in mouse models to the clinic to test their impact in patients.
Previously, the main treatments for cancer patients were surgery, radiation, and medicines with many unpleasant side-effects. The discovery that there are ways to turn our own defense system against cancer became a medical revolution. In some patients, this new treatment led to miracle cures that had never been seen before. The discovery was so incredible, it won a Nobel prize. Unfortunately, this new treatment does not work in as many patients as we would like. It is still a mystery why two people with the same cancer will respond differently to treatment, one patient might be cured and the other patient does not get better. This project is trying to figure out ways that will help doctors know who will be cured and who will not get better with this new treatment. We are developing a blood test to predict who will be cured before treatment begins. For those patients that are not likely to be cured, we are doing experiments to develop a medicine that can be added to the treatment in order to make the treatment cure many more patients.
Funded by Matthew Ishbia and the Dick Vitale Pediatric Cancer Research Fund
Childhood cancers of developing muscle are some of the most difficult to treat childhood cancers. Therapy has not significantly changed in the past 20 years and there isn’t even a meaningful new treatment being considered. Currently, even after the most intensive therapy possible, a third of these tumors will return and take the life of a child or young adult. We have taken a new approach using state-of-the-art methods to identify what we hope will be more targeted and less toxic treatments that yield better outcomes. We have already identified three new therapeutic avenues that we will test. The first is to ask if the abnormal gene that drives this disease, called PAX3-FOXO1, is a good drug target. We engineered the gene to be sensitive to a derivative of a known drug. While we can’t do this in kids, it allows us to ask what would happen if we had a drug? Second, we found that PAX3-FOXO1 turns on a small number of other genes, and we already have drugs that can target some of these. Third, we identified other possible drug targets that PAX3-FOXO1 recruits. We will test if these are key to causing cancer and if they would be good drug targets. We believe that our comprehensive approach gives us the best chance in the past 30 years to change the lives of these children with cancer, and to identify drugs or drug combinations that will be less toxic and yield better outcomes for these patients.
Funded by the Stuart Scott Memorial Cancer Research Fund
We believe that the immune system in patients witha precursor condition to multiple myeloma (a cancer in the bone marrow) allows the disease to progress (worsen) into more serious disease. Our project aims to find immune biomarkers that predict disease progression and identify patients who will likely progress early to treat the most at-risk patients before they become symptomatic. These markers may include changes in the number or type of immune cells or changes in the way those cells work. We will also examine how patients’ immune systems change in response to a new treatment that targets immune cells. We will use DNA and RNA sequencing and spatial imaging to investigate single cells from the bone marrow. We will gain a detailed picture of how the immune system supports or fights the tumor. This work will support the development of new treatments that may slow or stop disease progression.
Immunotherapy has transformed cancer therapy and positively impacted the lives of many patients. However, despite these advances, there remain barriers to the success of immunotherapy, and a majority of patients do not get better from immunotherapy. Unfortunately, soft tissue sarcomas are among the cancers which do not respond well to current immunotherapies, and the survival rate for these rare and difficult-to-treat cancers has barely improved for many years. Therefore, more research is needed to extend the benefits of immunotherapy to sarcoma patients.
The past decade has witnessed a big increase in research on natural killer (NK) cells. NK cells are a part of the immune system and are able to rapidly attack bacteria and cancer cells. Despite their ability to kill tumor cells, success with NK cells in cancer patients has hit roadblocks, in part because these cells lose killing capacity quickly, likely so the body can control them. This proposal seeks to understand how this exhaustion of NK cells can be overcome to better fulfill the promise of NK immunotherapy. We will block a novel receptor (TIGIT) on NK cells since this receptor is consistently upregulated on NK cells. We will use a diverse approach, including mice and human sarcoma samples. Then, we will pilot our new immunotherapy approach using NK cells and TIGIT blockade to release the brakes in a first-in-dog clinical trial for dog patients with soft tissue sarcomas. Cancer is a leading cause of death in dogs, as it is for humans.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Acute Myelogenous Leukemia (AML) is a cancer that is marked by the uncontrolled growth of immature cells of the myeloid lineage. Current therapies are often not effective, with therapy-resistant cancer cells leading to relapse and death in many patients, including both children and adults. Our goal is to develop a biologic that can block the growth and progression of myeloid leukemias. In previous work, we identified the cell surface protein Tetraspanin3 (Tspan3) as a key new regulator of AML, and showed that its inhibition led to a block in AML growth and improved survival in preclinical models. These data, as well as the successful antibody-mediated targeting of CD20, a tetraspanin-like molecule, provided a strong rationale for developing therapeutic monoclonal antibodies (mAbs) against Tspan3. Importantly, in conjunction with a CRO specializing in antibody development for biotech and pharma, we recently generated mAbs against Tspan3 that block the growth of human leukemia samples in vitro and in preclinical models in vivo. These highly promising data suggest that the antibodies we developed may be effective new therapeutics for targeting myeloid leukemia. To move this work forward towards the clinic, we now propose to determine if biomarkers can be identified to stratify patients for responsiveness to Tspan3 mAbs, develop a response signature to evaluate target engagement, and optimize the antibodies for use in human clinical studies. These studies are important because they have the potential to identify a new class of therapies for cancers that are largely unresponsive to current therapies.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Diffuse large B cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma in the U.S., is often curable with initial treatment. However, outcomes of the ~40% of patients who experience disease recurrence are dismal. Although stem cell transplantation and CAR T cell therapy salvage a subset of patients, most are not candidates for these aggressive treatments or will relapse after receiving them. Thus, relapsed DLBCL remains a critical area of unmet need. Recently, an immunotherapy that stimulates cancer cell engulfment by macrophages through blocking a “don’t eat me” protein called CD47 has shown promising activity in relapsed DLBCL patients when administered with the anti-CD20 antibody, rituximab. However, only 30-40% of patients achieve lymphoma regression after receiving this treatment. My laboratory has devised innovative approaches to enhance CD47 blockade therapy efficacy in relapsed DLBCL. First, by inhibiting a key signaling pathway in macrophages, we can enhance their “appetite” for DLBCL cells in the context of CD47 blockade in vitro. Second, we have developed tools necessary to execute an unbiased genetic screen to identify new and targetable “don’t eat me” proteins on DLBCL cells that enable their escape from macrophage phagocytosis. The major goals of this application are to: 1) enhance the in vivo efficacy of CD47 blockade therapy in DLBCL by disrupting a key macrophage signaling pathway, and 2) identify new “don’t eat me” proteins on lymphoma cells that can be targeted alone and in combination with CD47 blockade therapy. While DLBCL is our focus, many cancers employ mechanisms to evade engulfment. Thus, our results are expected to have broad cancer relevance.
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