Development of Adoptive T-Cell Therapy in Bladder Cancer Incorporating Patient-Specific Tumor Microenvironment
Abstract
There will be approximately 86,000 new cases of bladder cancer diagnosed in 2021 and approximately 17,000 bladder cancer deaths in the United States (U.S.). Many patients with early-stage disease require removal of the bladder – a potentially high risk and quality of life changing operation. For patients with advanced, metastatic disease, bladder cancer is uniformly fatal, with a life expectancy of slightly above 1 year. Overall, it has been estimated that smoking accounts for over 50% of new bladder cancer diagnoses, accounting for significant population disease burden which have worse clinical outcomes. This is particularly impactful for U.S. Veterans, who have a higher rate of bladder cancer and smoking compared to the non-Veteran population. Patients with bladder cancer have immune cells (T cells) that are capable of recognizing and killing tumor cells. These T cells are ineffective due to suppressive factors in the cancer patient that allows tumors to escape from recognition by T cells. One strategy to improve immune responses against tumors is adoptive cell therapy (ACT) using tumor-specific T cells. In this strategy, T cells are isolated from patient tumors and expanded in the laboratory to high numbers. This process allows the T cells to become re-activated and capable of killing tumor cells. The expanded T cells are transferred back to the patient as an immunotherapy. ACT with tumor-specific T cells has emerged as one of the most powerful therapies, resulting in a 50% response rate in patients with unresectable metastatic melanoma. This strategy can be applied to other tumor types such as bladder cancer. The research proposed in this application will improve the understanding of T cells in bladder cancer and explore efficacy and safety of delivery of in bladder tumor-infiltrating T lymphocytes (TIL) therapy to patients who have failed previous localized bladder treatments, with the ultimate goal of decreasing need for bladder removal. In addition, we will develop mathematical models to predict which patients will benefit from ACT TIL. The goals of this proposed research are: (1) Perform a phase 1/2 clinical trial to assess feasibility and toxicity of in bladder TIL therapy in patients who have failed BCG treatment, (2) To expand and characterize T cells expanded from bladder tumors, and (3) To develop a computational tool to stratify tumors based on their histology and clinical characteristics. As a consequence of these studies, we will gain a greater understanding of T cells in bladder cancer and provide the results to support the development of clinical trials of ACT in patients with bladder cancer that will be timely and impactful.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210341
Entities
People
- Shari Pilon-thomas
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army