T-cells expressing a chimeric-PD1-Dap10-CD3zeta receptor reduce tumour burden in multiple murine syngeneic models of solid cancer.

Adoptive transfer of T-cells is a promising therapy for many cancers. To enhance tumour recognition by T-cells, chimeric antigen receptors (CARs) consisting of signalling domains fused to receptors that recognize tumour-associated antigens can be expressed in T-cells. While CAR T-cells have shown clinical success for treating haematopoietic malignancies, using CAR T-cells to treat solid tumours remains a challenge. We developed a chimeric PD1 (chPD1) receptor that recognizes the ligands for the PD1 receptor that are expressed on many types of solid cancer. To determine if this novel CAR could target a wide variety of tumour types, the anti-tumour efficacy of chPD1 T-cells against syngeneic murine models of melanoma, renal, pancreatic, liver, colon, breast, prostate and bladder cancer was measured. Of the 14 cell lines tested, all expressed PD1 ligands on their cell surface, making them potential targets for chPD1 T-cells. ChPD1 T-cells lysed the tumour cells and secreted pro-inflammatory cytokines [interferon (IFN)γ, tumour necrosis factor (TNF)α, interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-17 and IL-21], but did not secrete the anti-inflammatory cytokine IL-10. Furthermore, T-cells expressing chPD1 receptors reduced an established tumour burden and led to long-term tumour-free survival in all types of solid tumours tested. ChPD1 T-cells did not survive longer than 14 days in vivo; however, treatment with chPD1 T-cells induced protective host anti-tumour memory responses in tumour-bearing mice. Therefore, adoptive transfer of chPD1 T-cells could be a novel therapeutic strategy to treat multiple types of solid cancer.