Document Type
Article
Publication Date
Spring 2024
Abstract
Chimeric antigen receptor (CAR) T cell therapy is a new promising therapy for hematopoietic malignancies. However, CAR T cells have yet to be successful in the treatment of solid tumors, including pediatric osteosarcoma and rhabdomyosarcoma. Changing the structure of CAR T cell receptors has been considered as a way to enhance the targeting of solid tumors. One method of changing the structure of CAR T cells is by changing the costimulatory domain. Inclusion of various costimulatory domains may alter many functions of CAR T cells, including serial killing, which is an important function needed to overcome the immunosuppressive microenvironment of solid tumors. We developed a novel CAR (chimeric PD-1, chPD1) that targets the programmed death 1 receptor (PD-1) ligands that are expressed on solid tumors. The aim of this study was to compare the inclusions of costimulatory domains, CD28, 411BB, Dap-10, GITR, and OX40, in the chPD1 receptor to see which were able to successfully induce serial killing of pediatric osteosarcoma and rhabdomyosarcoma cells. Three of the CAR T cell designs, chPD1-411BB, chPD1-Dap10, and chPD1-OX40 were successfully able to serially kill the cancer cells after two rechallenges. However, the other two CAR T cell designs, chPD1-CD28 and chPD1-GITR, showed a significant decrease in serial killing efficacy. In addition, T cells expressing chPD1- CD28 and chPD1-GITR receptors had reduced expression and release of killing proteins perforin, granzyme B, FasL and TRAIL on the third restimulation with tumor cells. Therefore, the differences observed in serial killing ability of chPD1-CD28 and –GITR expressing T cells may be partially due to a reduction in these killing proteins. Based on these results, chPD1-41-BB, chPD1-Dap10, and chPD1-OX40 expressing T cells may be promising treatments for pediatric osteosarcoma and rhabdomyosarcoma.
Recommended Citation
Wilkins, Kristen, "Costimulatory domains in chimeric antigen receptor T cells alter serial killing efficacy against pediatric rhabdomyosarcomas and osteosarcomas" (2024). Longwood Senior Theses. 31.
https://digitalcommons.longwood.edu/senior_theses/31
