IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor

Abstract

Infiltration, accumulation, and survival of chimeric antigen receptor T (CAR-T) cells in solid tumors is crucial for tumor clearance. We engineered CAR-T cells to express interleukin (IL)-7 and CCL19 (7 × 19 CAR-T cells), as these factors are essential for the maintenance of T-cell zones in lymphoid organs. In mice, 7 × 19 CAR-T cells achieved complete regression of pre-established solid tumors and prolonged mouse survival, with superior anti-tumor activity compared to conventional CAR-T cells. Histopathological analyses showed increased infiltration of dendritic cells (DC) and T cells into tumor tissues following 7 × 19 CAR-T cell therapy. Depletion of recipient T cells before 7 × 19 CAR-T cell administration dampened the therapeutic effects of 7 × 19 CAR-T cell treatment, suggesting that CAR-T cells and recipient immune cells collaborated to exert anti-tumor activity. Following treatment of mice with 7 × 19 CAR-T cells, both recipient conventional T cells and administered CAR-T cells generated memory responses against tumors.

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Figure 1: 7 × 19 CAR-T cells show improved immune function.
Figure 2: Complete regression of pre-established solid tumor by treatment with 7 × 19 CAR-T cells.
Figure 3: Infiltration of tumor tissues treated with 7 × 19 CAR-T cells by both T cells and DCs.

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Acknowledgements

This study is supported by research funds from Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) 14532963 (to K.T.), Practical Research for Innovative Cancer Control, and Project for Cancer Research and Therapeutic Evolution (P-CREATE) 16770206 (to K.T.), by Japan Agency for Medical Research and Development (AMED), and Noile-Immune Biotech Inc.

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K.A. and K.T. designed the experiments, analyzed the data, and wrote the manuscript; K.A., Y.K., T.N., N.O., and Y.S. produced CAR-T cells for the study; and K.A. performed the in vitro and in vivo experiments.

Corresponding author

Correspondence to Koji Tamada.

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Competing interests

K.T. and Y.S. hold stocks of Noile-Immune Biotech Inc. K.T. and Y.S. receive consulting fees from Noile-Immune Biotech Inc.

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Adachi, K., Kano, Y., Nagai, T. et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol 36, 346–351 (2018). https://doi.org/10.1038/nbt.4086

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