NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome

Mikiya Ishihara, Shigehisa Kitano, Shinichi Kageyama, Yoshihiro Miyahara, Noboru Yamamoto, Hidefumi Kato, Hideyuki Mishima, Hiroyoshi Hattori, Takeru Funakoshi, Takashi Kojima, Tetsuro Sasada, Eiichi Sato, Sachiko Okamoto, Daisuke Tomura, Ikuei Nukaya, Hideto Chono, Junichi Mineno, Muhammad Faris Kairi, Phuong Diem Hoang Nguyen, Yannick SimoniAlessandra Nardin, Evan Newell, Michael Fehlings, Hiroaki Ikeda, Takashi Watanabe, Hiroshi Shiku

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Because of the shortage of ideal cell surface antigens, the development of T-cell receptor (TCR)-engineered T cells (TCR-T) that target intracellular antigens such as NY-ESO-1 is a promising approach for treating patients with solid tumors. However, endogenous TCRs in vector-transduced T cells have been suggested to impair cell-surface expression of transduced TCR while generating mispaired TCRs that can become self-reactive. METHODS: We conducted a first-in-human phase I clinical trial with the TCR-transduced T-cell product (TBI-1301) in patients with NY-ESO-1-expressing solid tumors. In manufacturing TCR-T cells, we used a novel affinity-enhanced NY-ESO-1-specific TCR that was transduced by a retroviral vector that enables siRNA (small interfering RNA)-mediated silencing of endogenous TCR. The patients were divided into two cohorts. Cohort 1 was given a dose of 5×108 cells (whole cells including TCR-T cells) preconditioned with 1500 mg/m2 cyclophosphamide. Cohort 2 was given 5× 109 cells preconditioned with 1500 mg/m2 cyclophosphamide. RESULTS: In vitro study showed that both the CD8+ and CD4+ T fractions of TCR-T cells exhibited cytotoxic effects against NY-ESO-1-expressing tumor cells. Three patients and six patients were allocated to cohort 1 and cohort 2, respectively. Three of the six patients who received 5×109 cells showed tumor response, while three patients developed early-onset cytokine release syndrome (CRS). One of the patients developed a grade 3 lung injury associated with the infiltration of the TCR-T cells. No siRNA-related adverse events other than CRS were observed. Cytokines including interleukin 6 I and monocyte chemotactic protein-1/chemokine (C-C motif) ligand (CCL2)increased in the sera of patients with CRS. In vitro analysis showed these cytokines were not secreted from the T cells infused. A significant fraction of the manufactured T cells in patients with CRS was found to express either CD244, CD39, or both at high levels. CONCLUSIONS: The trial showed that endogenous TCR-silenced and affinity-enhanced NY-ESO-1 TCR-T cells were safely administered except for grade 3 lung injury. The TCR-T cell infusion exhibited significant tumor response and early-onset CRS in patients with tumors that express NY-ESO-1 at high levels. The differentiation properties of the manufactured T cells may be prognostic for TCR-T-related CRS. TRIAL REGISTRATION NUMBER: NCT02366546.

Original languageEnglish
JournalJournal for ImmunoTherapy of Cancer
Volume10
Issue number6
DOIs
Publication statusPublished - 2022 Jun 1

Keywords

  • cell engineering
  • clinical trials as topic
  • cytokines
  • immunotherapy, adoptive

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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