TY - JOUR
T1 - NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome
AU - Ishihara, Mikiya
AU - Kitano, Shigehisa
AU - Kageyama, Shinichi
AU - Miyahara, Yoshihiro
AU - Yamamoto, Noboru
AU - Kato, Hidefumi
AU - Mishima, Hideyuki
AU - Hattori, Hiroyoshi
AU - Funakoshi, Takeru
AU - Kojima, Takashi
AU - Sasada, Tetsuro
AU - Sato, Eiichi
AU - Okamoto, Sachiko
AU - Tomura, Daisuke
AU - Nukaya, Ikuei
AU - Chono, Hideto
AU - Mineno, Junichi
AU - Kairi, Muhammad Faris
AU - Diem Hoang Nguyen, Phuong
AU - Simoni, Yannick
AU - Nardin, Alessandra
AU - Newell, Evan
AU - Fehlings, Michael
AU - Ikeda, Hiroaki
AU - Watanabe, Takashi
AU - Shiku, Hiroshi
N1 - Funding Information:
This research was supported by the Medical Research and Development Programs Focused on Technology Transfer, Adaptable and Seamless Technology Transfer Program Through Target-driven R&D (A-STEP) from Japan Agency for Medical Research and Development, AMED (grant no 16im0110704s0104). Takara Bio supported the clinical trial and the exploratory research.
Funding Information:
SO, DT, IN, HC, and JM are employees of Takara Bio. The Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, to which SKa, YM, TW, and HS belonged, was funded by Takara Bio. MFK, PDHN, YS, AN, EN, and MF are employees or consultants of ImmunoScape. MI received honoraria from Chugai, Eisai, MSD, Ono Pharmaceutical, Daiichi Sankyo, and Eli Lilly. As a potential conflict of interest, SKi and NY received research grants from Takara Bio.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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.
AB - 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.
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U2 - 10.1136/jitc-2021-003811
DO - 10.1136/jitc-2021-003811
M3 - Article
C2 - 35768164
AN - SCOPUS:85133146959
SN - 2051-1426
VL - 10
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 6
M1 - e003811
ER -
