Deciphering immune cell heterogeneity and transcriptomic changes associated with CRS development and severity in CAR-T cell treated patients
Sylvain Simon
PhDFred Hutchinson Cancer Research Center
Project Term: January 1, 2021 - December 31, 2023
We seek to understand the mechanisms of Cytokine Release Syndrome (CRS), the most common and potentially life-threatening toxicity associated with CAR-T cell therapies. We are using cutting-edge approaches to determine the cascade of events leading to the development of CRS and therefore define new candidates for CRS prevention and/or resolution. We will describe a cellular and molecular atlas associated with CRS development and severity, thus providing more specific and reliable candidates for therapeutic targeting. These findings may inform strategies to prevent CRS of cancer patients receiving CAR-T therapies.
Blood cancers will account for approximatively 10% of all newly diagnosed cancers in the US in 2020. The Fred Hutchinson Cancer Research Center pioneered the use of bone marrow transplantation for leukemia and has a long history in developing innovative curative therapies for blood cancers. Our laboratory was one of the first to develop a personalized therapy called adoptive immunotherapy that uses the patient’s immune system to recognize and kill tumor cells. This therapy, called CAR T cell therapy, relies on immune cells called T lymphocytes (T cells) that are taken from the blood of cancer patients and then genetically engineered in the laboratory to recognize tumor cells. When administered back to the patient, these T cells can seek out and kill billions of cancer cells. While showing impressive clinical activity in leukemia and lymphoma, a limitation of CAR T cell therapy is the frequent development of a side effect called Cytokine Release Syndrome (CRS), caused by the over-activation of the patient’s immune system. Our understanding of the cells and molecules that drive CRS is still incomplete. Therefore, the drugs used to treat CRS and limit its severity are not specific and can also dampen the anti-tumor effects of the CAR-T therapy. The goal of our project is to thoroughly describe the molecular and cellular events driving the most serious cases of CRS and identify potential specific treatments that precisely tackle this complication. We will collect blood samples at multiple time points from 100 blood cancer patients who receive CAR therapy and develop CRS. Each sample will be studied using a network of four cutting-edge technologies to provide an atlas of the molecular and cellular networks that change before and during CRS. By collecting this unprecedented large quantity of information on CRS and collaborating with world-renowned experts for data analysis, we hope to better understand the factors that cause CRS and identify new targets for therapy. This study will describe the dynamic changes driving the disease and define early events that predict its severity. Candidate targets for treatment intervention will be evaluated in a novel laboratory model that we have developed. This work could lead to the development of next generation, safer, and more efficient CAR-T cell therapy for cancer patients. CRS is not restricted to CAR-T therapy and has been described in patients receiving other anti-cancer immunotherapies, as well as in severe viral infections including COVID-19. Thus, the findings from this project may have broad implications for human health.