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

Abstract

SummaryAdoptive 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.

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

“…Programmed cell death protein-1 (PD-1) is a famous immune checkpoint receptor that is involved in tumour immune evasion. In addition to small molecule inhibitors, chPD1 T cells have been designed to target PD1 precisely, and a preclinical study observed protective antitumour responses of chPD1 T cells in multiple models of solid tumours [180]. B7-H3 overexpressed on the PDAC cell surface is another attractive target, xenograft PDAC models certified the effectiveness of CAR-T targeting B7-H3, and 4-1BB co-stimulation enhanced this antitumour activity [181].…”

Identification of Circulating Biomarkers and Construction of a Prognostic Signature for Survival Prediction in Locally Advanced Pancreatic Cancer After Irreversible Electroporation

“…The regulation of tuft cells and stem cells of pancreatic cancer by IL-17A may contribute to tumor growth and progression. 26 Conversely, TNF-α was essential for the lysis of tumor cells induced by cytotoxic T cells 27 and played an important role in the polarization of macrophages into the M1-like subtype, 28 which could contribute to the phagocytosis of tumor cells and antigen-presentation. Moreover, it was shown that TNF-α was positively associated with IL-1ß, IL-2, and IL-6, which were also pro-inflammatory cytokines from M1-subtype macrophages.…”

Cell Therapies in Bladder Cancer Management

“…However, an increase in CAR-T cell doses to reach efficacy could induce toxicity due to off-target effects since an ideal antigen exclusively expressed in cancer cells has not been identified yet for solid tumors [ 44 ]. One alternative has recently been reported that uses a chimeric PD1 (chPD1) receptor that recognizes the ligands for the PD-1 receptor that are expressed in many types of solid cancer [ 51 ]. The engagement of PD1 receptor to PD1 ligand-expressing tumor cells triggered T cell induction via CD3ζ activating domain and co-stimulatory receptor DAP10 that enhances T cell effector responses.…”