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- Title
Autologous non‐human primate model for safety assessment of piggyBac transposon‐mediated chimeric antigen receptor T cells on granulocyte–macrophage colony‐stimulating factor receptor.
- Authors
Morokawa, Hirokazu; Yagyu, Shigeki; Hasegawa, Aiko; Tanaka, Miyuki; Saito, Shoji; Mochizuki, Hidemi; Sakamoto, Kengo; Shimoi, Akihito; Nakazawa, Yozo
- Abstract
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.
- Subjects
GRANULOCYTE-macrophage colony-stimulating factor; CHIMERIC antigen receptors; VASCULAR endothelial cells; KRA; T cells
- Publication
Clinical & Translational Immunology, 2020, Vol 9, Issue 11, p1
- ISSN
2050-0068
- Publication type
Article
- DOI
10.1002/cti2.1207