Author: Simoni, Yannick ; Miyahara, Yoshihiro ; Diem Hoang Nguyen, Phuong ; Watanabe, Takashi ; Ishihara, Mikiya ; Mineno, Junichi ; Newell, Evan ; Shiku, Hiroshi ; Mishima, Hideyuki ; Sato, Eiichi ; Hattori, Hiroyoshi ; Sasada, Tetsuro ; Nukaya, Ikuei ; Fehlings, Michael ; Kitano, Shigehisa ; Kairi, Muhammad Faris ; Ikeda, Hiroaki ; Kato, Hidefumi ; Yamamoto, Noboru ; Funakoshi, Takeru ; Kageyama, Shinichi ; Tomura, Daisuke ; Chono, Hideto ; Okamoto, Sachiko ; Nardin, Alessandra ; Kojima, Takashi

BackgroundBecause 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.MethodsWe 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.ResultsIn 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.ConclusionsThe 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 numberNCT02366546.

01 Sep 2015·Cancer CellQ1 · MEDICINE

Engineering Anti-myeloma Responses Using Affinity-Enhanced TCR-Engineered T Cells

Q1 · MEDICINE

Review

Author: Lasarte, Juan-Jose ; San Miguel, Jesus F ; Paiva, Bruno

NY-ESO-1 TCR-engineered T cells have shown activity in solid tumors. Recent work supports their use in multiple myeloma by showing that ex vivo antigen-specific expanded T cells traffic to and persist in bone marrow, are well tolerated, and produce promising response rates when infused after stem cell transplantation.

Cancer Cell International

NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route

Article

Author: Lin, Lihui ; Wang, Ling ; Ding, Xuanyan ; Amissah, Obed Boadi ; Chen, Wenfang ; Liu, Zhaoming ; Liu, Hohua ; Liang, Yalin ; Basnet, Rajesh ; Liu, Yujie ; de Dieu Habimana, Jean ; Li, Junyi ; Chen, Min ; Li, Zhiyuan ; Mukama, Omar ; Sun, Yirong ; Huang, Rongqi ; Lv, Lingshuang

AbstractBackgroundEsophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC.MethodsWe isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells.ResultsOur study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157–165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast.ConclusionOur findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

100 Deals associated with NY-ESO-1 TCR-T cell therapy (Shanghai Jibei biotechnology)

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Phase 1	CN	Shanghai Jibei Biotechnology Co., Ltd.	09 Jul 2020

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