The Role of Hypoxia on Tumor-Infiltrating Lymphocytes (TIL) from Renal Cell Carcinoma (RCC)
Abstract
In 2020, renal cell carcinoma (RCC) affected more than 70,000 Americans and caused more than 14,000 lives lost in the United States. Patients with metastatic RCC (mRCC) can have dramatic and durable responses to immune therapy, specifically checkpoint blockade (ICB) combinations. Approval of multiple ICB combinations has led to the recent change in first-line therapy options for patients with mRCC following over a decade of only modest progress. Nevertheless, in RCC patients, the response to ICB combinations is approximately 40%-50%, with complete responses in fewer than 10% of patients. Thus, only a minority of patients with mRCC have durable complete responses, and most patients will develop therapy resistance. Tumor-specific immune cells, T cells, are often present in the peripheral blood of cancer patients and infiltrate tumors, yet these T cells are generally unable to direct regression of bulky tumors. One major advance has been the success of adoptive T cell therapy (ACT) in which tumor-infiltrating T cells (TIL) are expanded and activated in the laboratory and then reinfused back into the cancer patient. Indeed, ACT with TIL has emerged as one of the most powerful therapies for the treatment of solid tumors. In unresectable metastatic melanoma, a 50% response rate is measured, raising the potential for this strategy to be applied to other tumor types. The long-term objective of this proposal is to develop a strategy of ACT with TIL as a curative approach for metastatic renal cell carcinoma to overcome resistance to ICB. It has been shown that renal cell tumors have low oxygen levels, a condition known as hypoxia. Hypoxia leads to the increased ability of tumors to grow and spread. Some studies have shown that T cells can be more reactive at low oxygen levels. Strategies to improve the expansion and function of T cells in hypoxic conditions may improve the efficacy of ACT with TIL in patients with renal cell carcinoma. We hypothesize that tumor-reactive TIL can be expanded from renal cell carcinomas and be optimized to exert effector functions under hypoxic conditions. We will evaluate the hypothesis through the following Specific Aims: (1) To optimize expansion of tumor-reactive TIL from patients with renal cell carcinoma. In this aim, we will evaluate strategies to improve the expansion of TIL from RCC tumors under hypoxic conditions. Positive results in this aim will lead to the development of clinically relevant protocols to expand TIL for patients with RCC. (2) To evaluate strategies to improve TIL activity in hypoxia. Using mouse models, we will evaluate the efficacy of ACT with TIL grown under various levels of hypoxia. The impact of our proposal, if we are successful in achieving our anticipated outcomes, will provide a solution to two FY21 KCRP Focus Areas: First, developing clinically relevant protocols to expand TIL for patients with RCC will lead to novel therapeutic strategies for the treatment of kidney cancer. Second, this proposal will support the development of the next generation of kidney cancer researchers, as the co-PI is an early career investigator. Furthermore, this proposal will cultivate collaborations in kidney cancer research. This collaboration between a genitourinary medical oncologist with clinical experience and a basic scientist with extensive experience in TIL protocols has led to the proposed studies, which are translational in nature. This novel multidisciplinary approach focuses on proof-of-concept studies that will optimize the design and execution of ACT clinical trials in patients with mRCC. Together, this team and the results of this study will be used to develop a clinical trial of ACT with TIL to treat patients with mRCC who do not respond to standard of care therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210606
Entities
People
- Shari Pilon-thomas
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army