Ken Hu, PhD

Parker Bridge Fellows Program; Funded in partnership between Parker Institute for Cancer Immunotherapy and the V Foundation

Cancer remains the second leading cause of death in the US. In order to tackle cancers, a new kind of therapy has emerged, termed immunotherapy, which aims to boost the immune system’s ability to fight the cancer. However, a major fraction of patients do not respond to immunotherapies currently. If we can figure out what other roadblocks to the immune system exist in these patients, we could expand the benefits to survival and quality of life to more people.  

The immune system is a complicated team, with different cell types doing different roles. In order to work together these cells must talk to each through cell signaling and have to be in the right formations to carry out a successful play against the tumor. We want to discover how this teamwork can break down and design therapies to patch those issues. 

The tumor is made up of more than just immune cells of course, and our project will focus on two types of cells that talk to the immune system. One cell type is the fibroblast which makes the building materials that hold our tissues together. Another cell type is the endothelial cell which forms blood vessels which serve as the roads and highways that carry cells, nutrients, and drugs into the tumor. If we can understand how these cells break immune cell teamwork, we can reveal new weak spots to target, making immunotherapies even stronger. 

Alex Herrera, MD

Funded by Lloyd Family Clinical Scholar Fund

New, non-chemotherapy treatments that use a patient’s own immune system have transformed the treatment of Hodgkin lymphoma (cHL). Typically used in patients with cHL that is resistant to standard treatment, these immune therapies can control the disease for months to years. However, in the long run, most patients will not be cured. Early research suggests that these powerful drugs are safe to use as part of the first or second treatment in patients with cHL and using them earlier could lead to more cures. However, we have not done the research to clarify when is the best time to use immune therapy in cHL and to determine which drugs are best to combine with immune therapy in order to cure more patients. 

My research will answer important questions about the best way to use immune therapy for cHL: (1) How should we use immune therapy as part of the first treatment to cure the most patients and reduce the side effects of our standard treatments? (2) How should we use immune therapy as the second treatment in patients who are not cured by their first treatment?  (3) Can we predict which patients will respond best to immune therapies to help us choose the patients most likely to benefit from these new treatments? And, in cHL patients who are resistant to immune therapy, can we reverse the resistance? 

Michael Evans, PhD

Funded by the Constellation Gold Network Distributors

Although cancer immunotherapies are beneficial for many patients, about half of patients fail to respond to treatment or may only respond for a short time.  Identifying which patients are benefitting from treatment is an important goal, as non-responders are subjected to needless treatment and deprived of potentially beneficial alternative therapies.  To address this challenge, we have developed a new PET scan to identify which patients are experiencing a tumor remission rapidly after the start of treatment.  We will first evaluate patients with non-Hodgkin’s lymphoma that are receiving CAR T cell therapy.  If our imaging technology successfully identifies patients that are responding to treatment, we expect it could also help patients with other types of cancer that are receiving immunotherapies.  Another long term goal will be to test if our imaging technology can help physicians understand if new immunotherapies in clinical trials can eliminate tumors. 

Christopher Seet, MD PhD

Harnessing the immune system to eliminate tumor cells has led to remarkable responses in several advanced cancer types. T cells are the key immune cell type which are engineered in the lab to seek out and destroy tumor cells, however in many cases tumor cells adapt to evade T cell killing, leading to disease relapses. Advances in cell engineering now permit T cells to be made in the lab from specialized stem cells. This technology promises to provide more cancer patients access to T cell therapies, but also presents the opportunity to make T cells more effective in prevent tumor escape. The goal of this research project is to study the ways in which tumor cells evade killing by lab-grown T cells, and how engineering specific molecules on lab-grown T cells may enable us to turn on tumor killing mechanisms to prevent tumor cell escape. Our overall goal is to further the development of this new kind of T cell therapy to be more effective across a wider range of cancer patients. 

Matthew Hangauer, PhD

Funded by the Wine Celebration

Cancer treatments often fail to produce durable responses and resistant tumors eventually regrow. This process presents a major clinical challenge and results in significant patient mortality. The molecular details of this process, termed acquired resistance, are poorly understood and there are currently no therapeutic options to prevent it. For cancer immunotherapy, acquired resistance is emerging as a prevalent phenomenon affecting approximately half of patients who initially respond to treatment. Key to this process are the leftover tumor cells which remain alive and seed resistant tumors. We have observed a small subpopulation of cancer cells which survive direct cytotoxic T cell attack over prolonged time periods. These cells, termed persister cells, survive through unknown mechanisms. In this proposal we will determine how persister cells survive despite undergoing T cell attack and also how a subset of persister cells eventually regrow and exhibit overt T cell resistance. If successful, our proposed work will shed light on acquired resistance to immunotherapy and may reveal new approaches to prevent tumors from recurring. 

Christopher Halbrook, PhD

Pancreatic cancer will soon become the second biggest cause of death from cancer in the United States. Patients usually find out they have this disease after it is too late for surgery. This leaves treatment as the only option, and the ones in use only help patients live for a few months. To change this, we need to find new approaches to improve the survival of our patients. 

Pancreatic cancer is hard to treat for many reasons. A key issue is that the tumors are made up of many cell types, not just cancer cells. Over the past few years, we have found ways these different cells can act together within a tumor to help cancers grow or avoid therapy. Most recently, we discovered that cancer growth can be slowed by blocking exchange of the amino acid asparagine when their mitochondria are stressed. 

The goal of this project is to show how cancer cells make and share asparagine. Knowing this, we can better target this metabolism to kill the cancer cells. From our previous work, we also predict this strategy will help patients better respond to immunotherapy. The results from this project will show us how to improve pancreatic cancer treatment and provide data we need to start new clinical trials. 

Robert Canter, MD

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. 

Tannishtha Reya, PhD

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. 

Silvio J. Gutkind, PhD

Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need

Cancer immunotherapies have led to major treatment breakthroughs for a number of different cancers, but the majority of head and neck cancer patients do not respond to immunotherapies, and clinical responses are often not durable.  Excitingly, we have demonstrated that targeting aberrant signaling networks in head and neck cancers can also influence anti-cancer immunity, supporting the development of novel, precision immune oncology therapies that significantly improve response profiles. The research outlined in this proposal will combine treatment with a targeted precision therapy – a highly selective anti-HER3 antibody – possessing both direct tumor and immune microenvironment activity, with PD-1 inhibitor immunotherapy. Leveraging our tobacco-signature oral cavity squamous cell carcinoma mouse model, we have obtained strong preliminary results supporting that our therapeutic combination – anti-HER3 + anti-PD-1 – 1) abolishes cancer-driving signaling pathways, 2) reverses the immunosuppressive microenvironment, and 3) potentiates existing antitumor immunity to achieve durable response. In order to develop more effective multimodal immune-oncology therapies that achieve durable response, we propose to employ several innovative techniques with single-cell level resolution to study the tumor-intrinsic effects of targeted HER3 blockade and how these changes ultimately invigorate and synergize with immunotherapies. Our novel approach represents a paradigm-shift in the design of cancer therapies – one in which therapies are rationally selected to target not only specific oncogenic pathways but also to activate cancer immunosurveillance. The proposed studies will provide the first signal-transduction based multimodal precision immunotherapy for head and neck cancer. 

Lourdes Baezconde-Garbanati, PhD

Funded in collaboration with ESPN

Even if cancer therapeutics and cures were found, they may not benefit African Americans and other under-represented minorities, due in part to a lack of participation in clinical cancer trials and cancer disparities research. Los Angeles has the seventh largest population of Blacks in the United States. Although many may think this population is homogeneous, there are still differences among individuals who identify as Blacks in Los Angeles. This population includes not only individuals born in the U.S. of African ancestry, but also foreign-born including of African or Afro-Caribbean origin. If we are to truly achieve “Victory over Cancer”, under-represented minorities, including all segments of the African American community need to engage in the research process. This grant will allow for holding focus groups with various segments of the AA community, achieving a greater understanding of barriers to CT and acceptance of precision medicine research. We will be able to obtain information for the creation of an outreach and awareness raising tool kit to work with AA community leaders, faith based and other organizations, in advancing knowledge and changing attitudes towards CT participation, provision of biospecimens and inclusion of AA communities in cancer disparities research.  

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