CAR T Cell Strategies to Counter Solid Tumor Antigen Immune Escape
Abstract
Scientific Objective/Rationale: Colorectal cancer often spreads to other organs (metastasize). Even though we are able to help extend survival by combining chemotherapies, targeted therapies, and surgically removing colon cancer that has spread to the liver, recurrence rates (chances the cancer comes back) are 50%. As a surgical oncologist who removes these tumors, I also see patients who have more advanced unresectable disease who have often had their tumors grow despite being on therapy. These observations underscore the need for more effective therapies that treat the whole body (called systemic therapy). Immunotherapies are a powerful systemic therapy that harness a patient’s immune system to attack the cancer. The clinical success of immune checkpoint blockade therapies that release the brakes on tumor-targeted T cells demonstrates how powerful T cells can be as an anti-cancer agent, yet this therapy is not effective in most colorectal cancers. We instead use gene-engineered T cell therapies, a type of immunotherapy where we take T cells and teach them to recognize and attack cancer cells. This is done by putting genetic material into T cells (gene-engineer) so they can express a receptor that allows them to attack and kill cancer cells (we use a receptor called a chimeric antigen receptor or CAR). Since T cells can persist for a long time (form memory) and can circulate throughout the blood, they have particular promise for treating even metastatic tumors and achieving long-term cancer survivors. However, while CAR T cell therapy has success in treating liquid malignancies (such as leukemias), treating solid tumors has not been successful. A major obstacle leading to treatment failure in solid tumors is antigen immune escape (AIE) by cells negative for the antigen targeted by T cells. Most CAR T cell formulations target just a single cancer antigen, allowing antigen-negative tumors to escape from attack and cause cancer recurrence. We have developed strategies that increase the number of antigens that are targeted by T cells, which we hypothesize will prevent AIE. These two strategies are to: (1) use CAR T cells programmed to recruit and activate new T cell immune responses by non-CAR T cells that are specific for additional mutated or non-mutated cancer antigens or (2) use CAR T cells that are able to target two antigens simultaneously. We perform experiments in clinically relevant immune competent mouse models and in mouse models using patient-derived tissues. Career Goals: As a surgeon, I have seen firsthand many patients whose colon cancers came back following surgical resection, highlighting the need for effective systemic treatments to increase the number of long-term survivors. The one goal that I am most committed to achieving as a clinician-scientist is to develop T cell therapies that can increase long-term survival in patients with metastatic colon cancer and other solid malignancies. The strategies we develop in this proposal can be applied to multiple other solid cancers/Topic Areas. Also, the cancer antigens we target with CAR T cells are shared by multiple other solid cancers. Receiving this award would provide me with the resources to publish high-impact manuscripts and generate preliminary data that can be used to obtain independent funding to support my laboratory. I am fortunate to have Dr. Renier Brentjens serve as career guide. He is a world leader in CAR T cell therapy who has led 12 CAR T cell clinical trials and has extensive experience mentoring junior faculty. He is an ideal mentor to guide me in establishing a nationally recognized and respected research program and become a leader in advancing immunotherapy to help patients. Applicability of Research: Solid cancers cause a majority of cancer-related deaths in active Service Members, Veterans, their families, and in the general population. At the conclusion of this award, we will have developed a more e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310439
Entities
People
- Leonid Cherkassky
Organizations
- United States Army