Autologous non-human primate model for safety assessment of piggyBac transposon-mediated chimeric antigen receptor T cells on granulocyte-macrophage colony-stimulating factor receptor

Clin Transl Immunology. 2020 Nov 22;9(11):e1207. doi: 10.1002/cti2.1207. eCollection 2020.


Objectives: Chimeric antigen receptor (CAR)-T cell therapy redirected to specific antigens on tumor cells is a promising immunotherapy strategy for various cancers. Most target antigens are also expressed on normal tissues at varying levels, and therefore, a considerable challenge in the field is determining safety profiles, including life-threatening off-tumor and off-target toxicities. The granulocyte-macrophage colony-stimulating factor receptor (hGMR) is a promising target for CAR T-cell therapy for a subset of acute myelocytic leukaemia, although it is also expressed on normal cells including monocytes, macrophages, CD34-positive haematopoietic cells and vascular endothelial cells. hGMR and other immune-related proteins are highly conserved between humans and cynomolgus macaques (Macaca fascicularis). Therefore, in this study, we engineered cynomolgus T cells to express CAR molecules redirected to hGMR by piggyBac (PB) transposon-based gene transfer and adoptively transferred autologous hGMR-CAR T cells into cynomolgus macaques.

Methods: We established PB-mediated human GMR (hGMR)-specific CAR T cells using cynomolgus peripheral blood mononuclear cells and transferred them into autologous individuals, and evaluated the potential toxicity related to hGMR-CAR T cells.

Results: hGMR-CAR T cells did not exert overt organ toxicities such as bone marrow suppression, monocytopenia and vasculitis, although they recognised and killed cynomolgus monocytes and macrophages in vitro.

Conclusion: Although our model did not simulate a tumor-bearing model, it supports the safety of hGMR-CAR T cells and demonstrates the usefulness of a non-human primate model to evaluate the safety of T-cell products by assessing off-tumor/off-target toxicity before clinical trials.

Keywords: CAR T cells; cynomolgus macaque; hGMR; non‐human primate; off‐tumor toxicity.