Article
作者: Newell, Evan ; Mineno, Junichi ; Kairi, Muhammad Faris ; Sato, Eiichi ; Kitano, Shigehisa ; Shiku, Hiroshi ; Funakoshi, Takeru ; Miyahara, Yoshihiro ; Kojima, Takashi ; Ikeda, Hiroaki ; Mishima, Hideyuki ; Yamamoto, Noboru ; Kageyama, Shinichi ; Fehlings, Michael ; Watanabe, Takashi ; Simoni, Yannick ; Sasada, Tetsuro ; Tomura, Daisuke ; Nukaya, Ikuei ; Diem Hoang Nguyen, Phuong ; Nardin, Alessandra ; Chono, Hideto ; Kato, Hidefumi ; Okamoto, Sachiko ; Ishihara, Mikiya ; Hattori, Hiroyoshi
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 5×108cells (whole cells including TCR-T cells) preconditioned with 1500 mg/m2cyclophosphamide. Cohort 2 was given 5× 109cells preconditioned with 1500 mg/m2cyclophosphamide.
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 5×109cells 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.