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

J Immunother Cancer. 2022 Jun;10(6):e003811. doi: 10.1136/jitc-2021-003811.


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.

Keywords: cell engineering; clinical trials as topic; cytokines; immunotherapy, adoptive.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Antigens, Neoplasm
  • Cyclophosphamide
  • Cytokine Release Syndrome* / therapy
  • Cytokines / metabolism
  • Humans
  • Immunotherapy*
  • Membrane Proteins
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Receptors, Antigen, T-Cell* / genetics
  • T-Lymphocytes* / immunology


  • Antigens, Neoplasm
  • CTAG1B protein, human
  • Cytokines
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • Cyclophosphamide

Associated data

  • ClinicalTrials.gov/NCT02366546