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

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

doi:10.1016/j.isci.2020.100998

Abstract

SummaryCurrent 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.

Highlights

Recent remarkable advances in cancer immunotherapy have taught us that cytotoxic T lymphocytes can kill tumor cells
SUMMARY 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
We developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from induced pluripotent stem cell (iPSC) 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

Summary

Introduction

Recent remarkable advances in cancer immunotherapy have taught us that cytotoxic T lymphocytes can kill tumor cells. T cells that are genetically modified to express exogenous antigen receptors by gene transfer have been shown to be effective (Morgan et al, 2006; Porter et al, 2011). One of such applications, in which peripheral T cells are transduced with a chimeric antigen receptor (CAR) gene that targets CD19, has shown dramatic efficacy against B cell leukemia/lymphoma (June and Sadelain, 2018). Transfer of T cell receptor (TCR) a/b genes targeting NY-ESO-1 or MART1 has been shown to be effective against various tumors (Klebanoff et al, 2016)

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