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Published on: May 12, 2023
NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release
Mikiya Ishihara1, Shigehisa Kitano2,3, Shinichi Kageyama4
1Cancer Center, Mie University Hospital, Tsu, Japan.
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.
Insights
T-cell receptor (TCR)-engineered T cells targeting NY-ESO-1 show promise for solid tumors. This trial demonstrated tumor response and early cytokine release syndrome (CRS) in patients, with differentiation properties potentially predicting CRS.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Targeting intracellular antigens like NY-ESO-1 with T-cell receptor (TCR)-engineered T cells (TCR-T) is a promising strategy for solid tumors due to limited cell surface antigen availability.
- Endogenous TCRs can interfere with the surface expression of introduced TCRs and lead to self-reactive T cells.
Purpose of the Study:
- To evaluate the safety and efficacy of a novel TCR-T cell therapy (TBI-1301) in a first-in-human Phase I clinical trial for patients with NY-ESO-1-expressing solid tumors.
- To assess the impact of siRNA-mediated silencing of endogenous TCR on the safety and efficacy of affinity-enhanced NY-ESO-1 TCR-T cells.
Main Methods:
- A Phase I clinical trial was conducted with two patient cohorts receiving different doses of TBI-1301 (NY-ESO-1-specific TCR-T cells) with cyclophosphamide preconditioning.
- TBI-1301 was manufactured using a retroviral vector enabling siRNA-mediated silencing of endogenous TCR and incorporating an affinity-enhanced TCR.
- In vitro studies assessed the cytotoxic effects of TCR-T cells against NY-ESO-1-expressing tumor cells.
Main Results:
- TCR-T cells demonstrated in vitro cytotoxic effects against NY-ESO-1-expressing tumor cells.
- Three of six patients in the higher dose cohort (5x10^9 cells) showed tumor response.
- Three patients developed early-onset cytokine release syndrome (CRS), and one experienced grade 3 lung injury; no siRNA-related adverse events other than CRS were observed.
Conclusions:
- Endogenous TCR-silenced, affinity-enhanced NY-ESO-1 TCR-T cells were safely administered, demonstrating significant tumor response in patients with high NY-ESO-1 expression.
- Early-onset CRS and a notable tumor response were observed, suggesting potential efficacy but also highlighting the need for managing immune-related toxicities.
- The differentiation characteristics of manufactured T cells may serve as a prognostic indicator for TCR-T-related CRS.
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