Cytotoxic T Lymphocytes Regenerated from iPS Cells Have Therapeutic Efficacy in a Patient-Derived Xenograft Solid Tumor Model

Soki Kashima; Takuya Maeda; Kyoko Masuda; Seiji Nagano; Takamitsu Inoue; Masashi Takeda; Yuka Kono; Takashi Kobayashi; Shigeyoshi Saito; Takahiro Higuchi; Hiroshi Ichise; Yuka Kobayashi; Keiko Iwaisako; Koji Terada; Yasutoshi Agata; Kazuyuki Numakura; Mitsuru Saito; Shintaro Narita; Masaki Yasukawa; Osamu Ogawa; Tomonori Habuchi; Hiroshi Kawamoto

doi:10.1016/j.isci.2020.100998

Cytotoxic T Lymphocytes Regenerated from iPS Cells Have Therapeutic Efficacy in a Patient-Derived Xenograft Solid Tumor Model

iScience. 2020 Apr 24;23(4):100998. doi: 10.1016/j.isci.2020.100998. Epub 2020 Apr 6.

Authors

Soki Kashima¹, Takuya Maeda², Kyoko Masuda², Seiji Nagano², Takamitsu Inoue³, Masashi Takeda⁴, Yuka Kono⁵, Takashi Kobayashi⁴, Shigeyoshi Saito⁶, Takahiro Higuchi⁷, Hiroshi Ichise², Yuka Kobayashi², Keiko Iwaisako⁸, Koji Terada⁹, Yasutoshi Agata⁹, Kazuyuki Numakura³, Mitsuru Saito³, Shintaro Narita³, Masaki Yasukawa¹⁰, Osamu Ogawa⁴, Tomonori Habuchi³, Hiroshi Kawamoto¹¹

Affiliations

¹ Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Department of Urology, Akita University Graduate School of Medicine, Akita, Japan; Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
² Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
³ Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
⁴ Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁵ Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁶ Department of Medical Physics and Engineering, Division of Health Sciences, Osaka University, Osaka, Japan.
⁷ Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Osaka, Japan.
⁸ Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
⁹ Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga, Japan.
¹⁰ Department of Hematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University, Matsuyama, Ehime, Japan.
¹¹ Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: kawamoto@infront.kyoto-u.ac.jp.

Abstract

Current adoptive T cell therapies conducted in an autologous setting are costly, time consuming, and depend on the quality of the patient's T cells. To address these issues, we developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from iPSCs that were originally derived from T cells and succeeded in regenerating CTLs specific for the WT1 antigen, which exhibited therapeutic efficacy in a xenograft model of leukemia. In this study, we extended our strategy to solid tumors. The regenerated WT1-specific CTLs had a strong therapeutic effect in orthotopic xenograft model using a renal cell carcinoma (RCC) cell line. To make our method more generally applicable, we developed an allogeneic approach by transducing HLA-haplotype homozygous iPSCs with WT1-specific TCR α/β genes that had been tested clinically. The regenerated CTLs antigen-specifically suppressed tumor growth in a patient-derived xenograft model of RCC, demonstrating the feasibility of our strategy against solid tumors.

Keywords: Cancer; Cellular Therapy; Immunological Methods.