Chimeric antigen receptor (CAR) T-cells are immune cells from patients that are engineered to target and kill cancers (not normal tissue). This is a new and exciting way to treat cancer. CARs have been wildly successful in treating children with leukemia that does not respond to any other therapy, saving many lives. I ran one of the first clinical trials to show this. Sadly, many patients experience severe or life-threatening side effects. The only drug that helps is currently on national shortage. This means some patients needing this lifesaving therapy may not get it. Even if that drug was available, CAR therapy still needs to be safer. We developed a chimeric inhibitory receptor (CIR) that we believe does just that. When it is combined with a CAR it dramatically decreases the production of the side effect causing proteins called cytokines. Importantly, it still kills tumors. Funding from this grant will allow us to make more versions of the CIR that can put the brakes on CARs in different ways. We will test the best ones in mice that have leukemia to confirm they still work. Results from these experiments will allow us to start a clinical trial of CIR-containing CAR T-cells for patients with leukemia or lymphoma here at the University of Virginia using our new CAR T-cell manufacturing facility. This unique approach to improving safety will have a dramatic impact on Virginians as well as all others with cancer who need life-saving CAR T-cell therapy.
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.
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.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Glioblastoma (GBM), the most common malignant brain tumor, is one of the most aggressive forms of cancer with limited therapeutic options and a dismal prognosis. The median survival of patients is 14.6 months. A significant barrier to treatment is the immunosuppressive tumor microenvironment (TME). A cancer vaccine is a form of immunotherapy that boosts the body’s defenses to fight cancer. We have developed personalized cancer vaccines based upon patient-specific neoantigens unique to a patient’s tumor to prime and boost immunity with the long-term goal to delay or prevent a recurrence. Twelve patients have been vaccinated with a peptide-based vaccine that incorporates up to ten personalized epitopes. Our preliminary results show induction of systemic immunity and an estimated favorable 6-month progression-free survival of 90.9% and 12-month survival from surgery date of 87.5%. We detected circulating antigen-specific cells in the blood that were apparent in ex vivo assays, suggesting priming of high-level responses. We now intend to apply new technologies (spatial sequencing, mass cytometry (CyTOF), imaging mass cytometry and O-link proteomics) to analyze the TME in GBM in depth, determine cross-talk of the tumor cells with the immune cells and other brain cells hijacked by the tumor to grow, and screen for circulating immune factors and their co-stimulatory and inhibitory molecules. The cellular and molecular profile and distribution of cells in the TME and the in-depth analysis of blood cells and soluble protein biomarkers will help predict response or resistance and identify new immunotherapy targets.
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.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Our immune systems are internal barometers for the primary response to foreign invaders like viruses and bacteria within our body. Despite cancer arising from irregular growth of our own cells, the immune system can effectively kill cancer cells just as it identifies and kills infected cells. However, cancer can also effectively hide from the immune response (known as immune evasion), specifically because it grows from our normal cells becoming mutated or unchecked. Thus, preventing immune evasion and augmenting the immune response are now the focus of new and promising treatments. The immune cells found in cancer can be classified by function, helpers, killers, and suppressors. Helpers educate the killers. Killers directly attack and eliminate the tumor cells. Suppressors hinder the immune response and promote cancer growth. Most immune-based therapies target the killers, however, there are many other components of the microenvironment in which cancer grows. In addition to the helpers and suppressors, the “soil” in which these cells thrive is important. We aim to understand how the “soil” (known as mesenchymal stem cells, MSCs) influences two key immune components in ovarian cancer patients, helper educational centers known as tertiary lymphoid structures (TLS) and suppressive T cells known as T regulatory cells (Tregs). Understanding this interplay is paramount to generating new and effective therapies for ovarian cancer patients, which is especially important in ovarian cancer because patients have not garnered the same therapeutic benefit with immune-based therapies as other solid tumors. In fact, only ~10% of ovarian cancer patients receive a survival benefit with immune-based therapies. Why is this? What is unique about ovarian cancer than allows it to effectively hide from the immune system?
In ovarian cancer, the balance of the immune response is often tipped to enhance the suppressors, thus killers cannot effectively target and kill the tumor cells. We aim to determine how to increase the “soil” (MSCs) that promotes helper TLS and prevents suppressive Tregs utilizing novel therapies. “Soil” cells which start in the bone marrow (BM-MSCs) can initiate the building of helper TLS. Thus, these BM-MSCs work with the immune system to increase anti-cancer immunity. “Soil” cells that develop within the ovarian cancer environment (CA-MSCs) can help enhance ovarian cancer growth by amplifying the suppressive function of Tregs. Thus, these local CA-MSCs work against the immune system to decrease anti-cancer immunity.
Altering the immune balance by targeting both the immune cells and the MSCs offers powerful new combinatorial treatment approaches. Our goal is to understand the specific factors within the ovarian cancer environment which impact this immune balance and to develop treatments to shift this balance to kill ovarian cancer. Specifically, we will study the steps necessary for BM-MSCs to support TLS formation and immune activation. We will also identify how local CA-MSCs recruit Tregs to decrease the immune response. We will specifically test if blocking the interaction between CA-MSCs and Tregs will shift the balance of immunity towards killing cancer.
This work can be quickly moved into clinical trials as the blocking drug we are testing (neuropilin-1; NRP1) is already in early clinical development and our team includes an ovarian cancer clinician and translational immunologist with experience writing, conducting and analyzing clinical trials. The vision of the Clinic and Laboratory Integration Program (CLIP) is to improve the effectiveness of cancer immunotherapies. This grant will meet this vision by developing a therapy that targets MSCs and the immune system for a synergistic effect on improved patient outcomes.
Funded in partnership with Miami Dolphins Foundation
Vitamins play an essential role in keeping our immune system healthy by maintaining normal blood cell production. Certain types of vitamins can also help in the prevention and treatment of blood cancers. Vitamin A has been used for decades to treat a subset of blood cancer patients with defects in a protein that relies on vitamin A for its normal activity. More recently, our work has shown that vitamin C can also stop blood cancers from forming, and slow cancer growth, by maintaining or restoring the activity of a protein known as TET2. Loss of TET2 function causes an increase in the growth of blood cells that drive cancer development. Mutations in TET2 that lower its activity are frequently found in patients with blood cancers. TET2 is also frequently defective in the blood cells of the healthy elderly population that can put them at a much greater risk of developing a blood cancer. The goal of our work is to understand how we can maintain TET2 activity to prevent and block cancers of the blood. Interestingly, vitamin A treatment can increase TET2 levels in cells, which in combination with vitamin C restores TET2 activity more than either treatment alone to stop the growth of blood cancer. Our goal in this study is to model combination treatment strategies of vitamin A and vitamin C to prevent blood cancer formation and growth that can be used as a potential therapy to treat blood cancer patients with a loss in TET2 activity.
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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