Chimeric antigen receptors (CAR) utilize costimulatory domains to enhance anti-tumor efficacy. However, it is unclear which costimulatory domain is preferable. Therefore, the intracellular domains of CD28, Dap10, 41BB, GITR, ICOS, or OX40 were compared in a murine chimeric PD1 (chPD1) receptor that targets tumor-associated PD1 ligands. Upon antigen restimulation, T cells expressing chPD1-CD28 receptors had reduced lytic capacity. While most of the chPD1 T cell receptors secreted pro-inflammatory (IFNã, TNFá, IL-2, GM-CSF, IL-17, and IL-21) and anti-inflammatory cytokines (IL-10), chPD1-Dap10 did not secrete IL-10. Furthermore, chPD1-Dap10 and -41BB receptors induced a memory precursor phenotype, had enhanced persistence in vivo, and superior therapeutic efficacy in murine models of T cell lymphoma and melanoma compared to chPD1-CD28 or chPD1-GITR expressing T cells. Therefore, each costimulatory domain induces differential effects in CAR-expressing T cells and inclusion of Dap10 or 4-1BB costimulatory domains may induce a preferential cytokine profile and differentiation for cancer therapy.
4-1BB Ligand Animals