Adoptive transfer of murine T cells expressing a chimeric‐ PD 1‐Dap10 receptor as an immunotherapy for lymphoma

Summary Adoptive transfer of T cells is a promising cancer therapy and expression of chimeric antigen receptors can enhance tumour recognition and T‐cell effector functions. The programmed death protein 1 ( PD 1) receptor is a prospective target for a chimeric antigen receptor because PD 1 ligands are expressed on many cancer types, including lymphoma. Therefore, we developed a murine chimeric PD 1 receptor (ch PD 1) consisting of the PD 1 extracellular domain fused to the cytoplasmic domain of CD 3ζ. Additionally, chimeric antigen receptor therapies use various co‐stimulatory domains to enhance efficacy. Hence, the inclusion of a Dap10 or CD 28 co‐stimulatory domain in the ch PD 1 receptor was compared to determine which domain induced optimal anti‐tumour immunity in a mouse model of lymphoma. The ch PD 1 T cells secreted pro‐inflammatory cytokines and lysed RMA lymphoma cells. Adoptive transfer of ch PD 1 T cells significantly reduced established tumours and led to tumour‐free survival in lymphoma‐bearing mice. When comparing ch PD 1 receptors containing a Dap10 or CD 28 domain, both receptors induced secretion of pro‐inflammatory cytokines; however, ch PD 1‐ CD 28 T cells also secreted anti‐inflammatory cytokines whereas ch PD 1‐Dap10 T cells did not. Additionally, ch PD 1‐Dap10 induced a central memory T‐cell phenotype compared with ch PD 1‐ CD 28, which induced an effector memory phenotype. The ch PD 1‐Dap10 T cells also had enhanced in vivo persistence and anti‐tumour efficacy compared with ch PD 1‐ CD 28 T cells. Therefore, adoptive transfer of ch PD 1 T cells could be a novel therapy for lymphoma and inclusion of the Dap10 co‐stimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile and T‐cell differentiation phenotype for anti‐tumour therapies.