NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome. Issue 6 (29th June 2022)

• Record Type: Journal Article
• Authors: Ishihara, Mikiya; Kitano, Shigehisa; Kageyama, Shinichi; Miyahara, Yoshihiro; Yamamoto, Noboru; Kato, Hidefumi; Mishima, Hideyuki; Hattori, Hiroyoshi; Funakoshi, Takeru; Kojima, Takashi; Sasada, Tetsuro; Sato, Eiichi; Okamoto, Sachiko; Tomura, Daisuke; Nukaya, Ikuei; Chono, Hideto; Mineno, Junichi; Kairi, Muhammad Faris; Diem Hoang Nguyen, Phuong; Simoni, Yannick; Nardin, Alessandra; Newell, Evan; Fehlings, Michael; Ikeda, Hiroaki; Watanabe, Takashi; Shiku, Hiroshi
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 6(2022)
• Publication Date: 2022-06-29
• Subjects: cell engineering -- clinical trials as topic -- cytokines -- immunotherapy, adoptive; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-003811
• Languages: English
• ISSNs: 2051-1426

Abstract

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 5×10 8 cells (whole cells including TCR-T cells) preconditioned with 1500 mg/m 2 cyclophosphamide. Cohort 2 was given 5× 10 9 cells preconditioned with 1500 mg/m 2 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 5×10 9 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 .