Characterizing and Targeting the Microenvironmental Barriers to Immunotherapeutic Response in Renal Cell Carcinoma
Abstract
In recent years, cancer treatments that use the power of the immune system to attack tumors--known as immunotherapies--have shown exceptional promise. Among these, immune checkpoint inhibitors (ICI) allow cancer cells to be recognized and destroyed by a patients own immune cells (specifically T cells), often with fewer side effects than conventional chemotherapy or radiation. These new drugs can shrink or even eliminate tumors and keep them from coming back. ICIs are now considered standard treatment for very advanced kidney cancers, as large clinical trials led by our group and others have shown them to be effective. Nevertheless, many patients do not respond to these therapies. Understanding the basis of sensitivity and resistance to ICIs in kidney cancer patients is essential to making them work for more patients. To increase the effectiveness of ICIs, researchers are conducting trials of ICIs in combination with drugs that block the growth of blood vessels. The results so far suggest that this works better than giving ICIs alone, but we still lack information on which patients are most likely to benefit from the combination. The objective of our proposed research project is to identify the mechanisms underlying sensitivity and resistance to ICIs in patients with renal cell carcinoma (RCC), and to use that knowledge to find new ways of overcoming resistance to ICIs in this cancer. Within that broad objective, we have three specific goals. First, we will determine which features of cancer cells (such as the number of mutations or other genetic changes) and their environment (such as the number and types of immune cells in the tumor) are more frequent in patients who respond to ICIs and inhibitors of blood vessel growth compared with those who do not. Second, we will utilize and further develop mouse models of kidney cancer to test and optimize combinations of ICIs with other therapies. Our research so far indicates that another type of immune cell in kidney tumors, called macrophages, become disordered in a way that keeps the immune response turned off. Therefore, one of the combinations we will test will include a drug that reduces the number of macrophages. Other combinations will be informed by the results of our work toward the first goal. Lastly, we will investigate a problem called acquired resistance, in which a tumor that initially responds to treatment acquires the ability to resist treatment. Because acquired resistance is a common problem for patients treated with ICIs, we will determine the changes to tumor genetics and tumor environment that confer acquired resistance. Our work will advance our understanding of why sensitivity to immunotherapies varies among patients with kidney cancer and may lead to novel combinations of ICIs with other anticancer drugs, whose ability to overcome resistance could be tested in future clinical trials. If successful, we believe this work will generate new insights into which patients with RCC will respond to ICIs and help oncologists better decide whether ICI is a good treatment option for a given patient.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910792
Entities
People
- Abraham Hakimi
Organizations
- Sloan-Kettering Institute
- United States Army