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Enhanced anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells in orthotopic and patient-derived xenograft tumor models

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Abstract

Chimeric antigen receptor (CAR)-T cell therapy has impressive efficacy in hematological malignancies, but its application in solid tumors remains a challenge. Multiple hurdles associated with the biological and immunological features of solid tumors currently limit the application of CAR-T cells in the treatment of solid tumors. Using syngeneic mouse models, we recently reported that CAR-T cells engineered to concomitantly produce interleukin (IL)-7 and chemokine (C–C motif) ligand 19 (CCL19)-induced potent anti-tumor efficacy against solid tumors through an improved ability of migration and proliferation even in an immunosuppressive tumor microenvironment. In this study, for a preclinical evaluation preceding clinical application, we further explored the potential of IL-7/CCL19-producing human CAR-T cells using models that mimic the clinical features of solid tumors. Human anti-mesothelin CAR-T cells producing human IL-7/CCL19 achieved complete eradication of orthotopic pre-established malignant mesothelioma and prevented a relapse of tumors with downregulated antigen expression. Moreover, mice with patient-derived xenograft of mesothelin-positive pancreatic cancers exhibited significant inhibition of tumor growth and prolonged survival following treatment with IL-7/CCL19-producing CAR-T cells, compared to treatment with conventional CAR-T cells. Transfer of IL-7/CCL19-producing CAR-T cells resulted in an increase in not only CAR-T cells but also non-CAR-T cells within the tumor tissues and downregulated the expression of exhaustion markers, including PD-1 and TIGIT, on the T cells. Taken together, our current study elucidated the exceptional anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells and their potential for clinical application in the treatment of patients with solid tumors.

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Availability of data and material

The datasets generated and analyzed during the current study are available from the corresponding author upon a reasonable request.

Abbreviations

CAR:

Chimeric antigen receptor

DCs:

Dendritic cells

E:T:

Effector to target

IL:

Interleukin

IFN:

Interferon

I.v.:

Intravenously

NSG:

NOD.Cg-PrkdcscidIl2rgtm1Wjl/Szj

PD-1:

Programed cell death 1

PDX:

Patient-derived xenograft

S.c.:

Subcutaneously

ScFv:

Single-chain variable fragment

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

TILs:

Tumor-infiltrating lymphocytes

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Acknowledgment

The authors would thank Drs. Daisuke Umezu, Jun Mori, Takahiro Sasaki, Yasunori Iida for excellent advices on the study. The authors would also thank Hiromi Kurosawa, Mihoko Ida, Nana Okada, Makiko Miyamoto, Satoshi Tatekabe, Nanami Nakamura, and Chisaki Mochida for their excellent technical supports.

Funding

This study was supported by 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 Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (C) Grant Number 19K07625 (to Yu.S.).

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Authors and Affiliations

  1. Department of Immunology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Shunsuke Goto, Yukimi Sakoda, Keishi Adachi & Koji Tamada

  2. Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    Shunsuke Goto & Masatoshi Eto

  3. Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Japan

    Yoshitaka Sekido

  4. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    Seiji Yano

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  1. Shunsuke Goto
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  2. Yukimi Sakoda
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  3. Keishi Adachi
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Contributions

S.G., Yu.S., K.A. and K.T. designed the study and interpreted the data; S.G. performed the experiments and analyzed the data; Yo.S. and S.Y. provided the materials; M.E. and K.T. supervised the study; S.G. and K.T. wrote the manuscript.

Corresponding author

Correspondence to Koji Tamada.

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Conflicts of interest

K.T. and Yu.S. hold stocks of Noile-Immune Biotech Inc., and receive remuneration from Noile-Immune Biotech Inc. Other authors declare no conflict of interest.

Ethical approval

All animal procedures were approved by the Institutional Animal Care and Use Committee of the Yamaguchi University. Human PBMCs were derived from healthy volunteers who gave a written informed consent. Patient-derived xenograft tumor was derived from a pancreatic cancer patient who gave written informed consent. This study was approved by the ethics committee of the Yamaguchi University.

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Goto, S., Sakoda, Y., Adachi, K. et al. Enhanced anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells in orthotopic and patient-derived xenograft tumor models. Cancer Immunol Immunother 70, 2503–2515 (2021). https://doi.org/10.1007/s00262-021-02853-3

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