Design and Testing of Dual-Targeted Fine-Tuned Immune-Restoring (DFIR) CAR T-Cell Therapy to Achieve Cures of High-Grade Serous Ovarian Cancer
Abstract
Ovarian cancer is often diagnosed late, and treatment for stage III or IV disease is rarely curative with 5-year survival rates under 20%. However, no effective therapy is available for relapsed or metastatic disease that has failed first-line therapy. Recent trials involving the new immunotherapy agents known as immune checkpoint inhibitors such as anti-PD(L)1 monoclonal antibodies have also shown poor clinical results. Active and retired women of the military deserve the very best treatment that we can offer in return for their valiant service to our country. There is an urgent need for more effective therapies to treat our military women and our proposal offers hope that a breakthrough therapy for high-grade serous ovarian cancer (HGSOC) can be discovered. Chimeric Antigen Receptor (CAR) T cell therapy is a new type of living drug that holds promise for the Cure of OvCA. This therapy takes advantage of our own immune cells and engineers them to recognize and kill cancer cells. These CAR-T therapies have shown clinically meaningful results for the treatment of hematologic malignancies which has resulted in three FDA-approved drugs; however, these findings have not been readily translated to solid tumors. Several major hurdles have been recognized that limit our ability to achieve cures of solid tumors using CAR-T cells. To address these issues, we have designed Dual-targeted, Fine-tuned, Immune Restoring (DFIR) CAR-T cells for the treatment of solid tumors with an emphasis on improving anti-tumor efficacy and patient safety. The project that we propose is based on new information that we have obtained from the analysis of patient HGSOC tumors. We will first construct DFIR CAR-T cells and test their ability to kill HGSOC tumors in tissue culture. Importantly, our therapy also restores anti-tumor immunity of the patient immune cells that arrive at the tumor but quickly become exhausted. Following these studies, we will perform DFIR CAR-T treatment studies in humanized mice with the goal of cures of the HGSOC tumors. Humanized mice are mice that are engineered to carry a human immune system. Our analyses will also be aimed at understanding the mechanism by which the DFIR CAR-T cells work to restore anti-tumor immunity and is an important part of our studies. Finally, DFIR CAR-T cells should remain in the patient for life where they can constantly monitor by a process we call immune surveillance to prevent new HGSOC cells from arising. This cellular combination immunotherapy is formulated to be administered as a one-time, single agent, which should also decrease the burden on the patient, clinician, and payer. We believe that this DFIR CAR-T therapy offers tremendous potential for treatment of our Warfighters and military Service Members who deserve the very best.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210355
Entities
People
- Wayne A Marasco
Organizations
- Dana–Farber Cancer Institute
- United States Army