Improving Chimeric Antigen Receptor (CAR) T-Cell Trafficking and Penetration in Solid Tumor Malignancies
Abstract
Hypothesis and Rationale: Chimeric Antigen Receptor (CAR) T-cell immunotherapy is a modality wherein T-cells are collected from a patient and modified to express a receptor that targets them to tumor cells. When these modified T-cells, now CAR T-cells, are infused back into the patient, they seek out and eradicate the tumor. This treatment has been very active and has now been Food and Drug Administration-approved for certain blood cancers. However, due to the different composition of solid tumors such as ovarian cancer, this treatment has not shown a similar degree of efficacy. We have made progress in modifying CAR T-cells to make them more potent against ovarian cancer, but little is known about how they traffic to the tumor. This research proposal sets out to dissect the mechanisms of how CAR T-cell traffic to ovarian cancer and to use this knowledge to further enhance CAR T-cell efficacy. We hypothesize that CAR T-cells targeted to ovarian cancer can be further engineered to improve tumor-directed trafficking by overexpressing chemokine receptors and transcriptional activation factors. Furthermore, these modifications can be combined with established modalities to improve CAR T-cell efficacy comprehensively. Principal Investigator’s (PI’s) Career Goals in Ovarian Cancer Research: My goal is to improve the efficacy of immunotherapy for ovarian cancer. We know that these types of treatment can be very effective for several other types of cancer, including melanoma, lung, and bladder cancer. Dedicated ovarian cancer researchers focusing on the unique biology of ovarian cancer and designing solutions for this disease are urgently needed. PI Participation in and Contribution to the Growth of the Ovarian Cancer Academy: The Ovarian Cancer Academy will provide me with funding, expanded mentorship, and the research community that will significantly enhance my success. Funding for translational research in CAR T-cell therapy for ovarian cancer is limited. In addition, experienced mentors and cross-disciplinary research are rare. The Ovarian Cancer Academy not only solves these problems but also provides me an opportunity to share my research and collaborate with and mentor others who are focused on curing ovarian cancer. Ultimate Applicability of the Research: At the completion of this project, we will have designed and evaluated enhanced CAR T-cells that can efficiently seek out ovarian cancer and eradicate it anywhere in the body. Once we have concluded all of the preclinical experiments outlined in this proposal, we will conduct clinical trials in patients with ovarian cancer. We have done this with our prior CAR T-cells, which are currently undergoing clinical trial testing. Likely Contributions of This Study to Advancing Our Knowledge of Ovarian Cancer: This is the first study dedicated solely to understanding the limitations of how CAR T-cells seek out ovarian cancer tumors. This knowledge will be used to not only enhance the efficacy of CAR T-cells, but can also be used to design better agents and drugs that work synergistically with immunotherapy. The Potential Impact of the Proposed Research on the Health and Well-Being of All Women Impacted by This Disease: Women with ovarian cancer who have relapsed will eventually develop multidrug-resistant disease. Harnessing the immune system to treat these cancers is a potential solution to this problem because immune cells can be co-adapted to the tumor to prevent resistance. Furthermore, immunotherapy has the potential to render some patients entirely disease-free and prevent the cancer from coming back. We have seen these types of benefits for patients with blood cancers treated with CAR T-cells. Further research, such as the one we are proposing, is required to replicate similar results in patients with ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010562
Entities
People
- Oladapo Yeku
Organizations
- Massachusetts General Hospital
- United States Army