Adoptive transfer of murine T cells expressing a chimeric- PD1-Dap10 receptor as an immunotherapy for lymphoma.

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 ( PD1) receptor is a prospective target for a chimeric antigen receptor because PD1 ligands are expressed on many cancer types, including lymphoma. Therefore, we developed a murine chimeric PD1 receptor (ch PD1) consisting of the PD1 extracellular domain fused to the cytoplasmic domain of CD3ζ. Additionally, chimeric antigen receptor therapies use various co-stimulatory domains to enhance efficacy. Hence, the inclusion of a Dap10 or CD28 co-stimulatory domain in the ch PD1 receptor was compared to determine which domain induced optimal anti-tumour immunity in a mouse model of lymphoma. The ch PD1 T cells secreted pro-inflammatory cytokines and lysed RMA lymphoma cells. Adoptive transfer of ch PD1 T cells significantly reduced established tumours and led to tumour-free survival in lymphoma-bearing mice. When comparing ch PD1 receptors containing a Dap10 or CD28 domain, both receptors induced secretion of pro-inflammatory cytokines; however, ch PD1- CD28 T cells also secreted anti-inflammatory cytokines whereas ch PD1-Dap10 T cells did not. Additionally, ch PD1-Dap10 induced a central memory T-cell phenotype compared with ch PD1- CD28, which induced an effector memory phenotype. The ch PD1-Dap10 T cells also had enhanced in vivo persistence and anti-tumour efficacy compared with ch PD1- CD28 T cells. Therefore, adoptive transfer of ch PD1 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. [ABSTRACT FROM AUTHOR]