Document Type
Article
Publication Date
5-2-2025
Abstract
Acute lymphocytic leukemia (ALL) is a common pediatric cancer that is characterized by its high incidence of relapsed and refractory (R/R) cases. This brings about a need for new treatments that are safe and effective. One type of novel cancer immunotherapy uses chimeric antigen receptor (CAR) expressing T cells. CARs target tumor-associated antigens and enhance T cell responses. CAR T cell therapy has been successful in treating ALL, however there are associated toxicities such as cytokine release syndrome (CRS). One potential way to reduce CRS is to inhibit cytokine secretion and to alter the costimulatory domain in the CAR T cell. Therefore, we developed CAR T cells containing different costimulatory domains to test the role of costimulation in CRS induction. We used a chimeric-PD1 (chPD1) receptor with the Programmed Death 1 receptor as the tumor-targeting domain. The purpose of this study was to evaluate whether T cell secretion of inflammatory cytokines was required for tumor cell cytotoxicity and release of CRS-inducing inflammatory molecules. Additionally, if inclusion of costimulatory domains, CD28, 4-1BB, and Dap10, in the chPD1 receptor altered tumor cell cytotoxicity and cytokine secretion was evaluated. ChPD1 T cells had significant tumor cell killing compared to control T cells. Compared to 4-1BB and Dap10, inclusion of CD28 in the chPD1 receptor increased secretion of CRS-related cytokines. Blocking antibodies were used to test the requirement of T-cell cytokine secretion in CRS induction. Blockade of IFN-γ, GM-CSF, and IL-10 alone or in combination did not decrease tumor cell death. However, blockade of these cytokines did alter release of CRS-related molecules NO, TNF-α, and IL-6 from activated leukocytes. Therefore, blocking chPD1 derived cytokines could reduce the induction of CRS, and the inclusion of 4-1BB and Dap10 could provide safer costimulation for chPD1 CAR T cell therapy used against ALL.
Recommended Citation
Cohen, Grace, "Blockade of chPD1 T cell derived cytokines decreases inflammatory molecules related to cytokine release syndrome in acute lymphocytic leukemia" (2025). Longwood Senior Theses. 45.
https://digitalcommons.longwood.edu/senior_theses/45
