人类端粒酶逆转录酶（hTERT）是抗癌治疗的一个有吸引力的靶点。我们开发了一种有效的方法，使用实体癌症患者的外周血单个核细胞（PBMC）生成hTERT特异性CD8+ T细胞（hTERT诱导的自然T细胞[TERTiNTs]），并研究了其可行性和安全性。这是一个单中心的1期试验，采用3+3剂量递增设计评估了TERTiNTs的6个剂量水平。使用hTERT肽段面板对每个患者的PBMC进行筛选，以选择刺激CD8+ T细胞的细胞。选择最具刺激性的四个肽段用于从对标准治疗具有耐药性或不耐受性的患者产生自体CD8+ T细胞。符合条件的患者接受不同剂量水平（4×108细胞/m2，8×108细胞/m2和16×108细胞/m2）的TERTiNTs的单次静脉输注。给予预处理化疗，包括顺铂单独或与氟达拉滨联合使用，以诱导淋巴细胞减少。自2014年1月至2019年10月，共纳入24名具有中位数为三个前期治疗的患者。最常见的不良事件是淋巴细胞减少（79.2%），恶心（58.3%）和中性粒细胞减少（54.2%），主要由于预处理化疗引起。TERTiNTs治疗的输注耐受性良好，无剂量限制性毒性观察到。没有患者显示出客观反应。7名患者（30.4%）达到稳定的疾病，中位无进展生存为3.9个月（范围，3.2-11.3）。在最高剂量水平（16×108细胞/m2），5名患者中有4名显示出疾病稳定。TERTiNTs的生成可行且安全，并在重度预治疗癌症患者中提供了有趣的疾病控制率。© 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.

Human telomerase reverse transcriptase (hTERT) is an attractive target for anti-cancer therapies. We developed an effective method for generating hTERT-specific CD8+ T cells (hTERT-induced natural T cells [TERTiNTs]) using peripheral blood mononuclear cells (PBMCs) from patients with solid cancers and investigated their feasibility and safety.This was a single-center phase 1 trial using a 3 + 3 dose escalation design to evaluate six dose levels of TERTiNTs. PBMCs from each patient were screened using an hTERT peptide panel to select those that stimulated CD8+ T cells. The four most stimulatory peptides were used to produce autologous CD8+ T cells from patients refractory or intolerant to standard therapies. Eligible patients received a single intravenous infusion of TERTiNTs at different dose levels (4 × 108 cells/m2, 8 × 108 cells/m2 and 16 × 108 cells/m2). Pre-conditioning chemotherapy, including cyclophosphamide alone or in combination with fludarabine, was administered to induce lymphodepletion.From January 2014 to October 2019, a total of 24 patients with a median of three prior lines of therapy were enrolled. The most common adverse events were lymphopenia (79.2%), nausea (58.3%) and neutropenia (54.2%), mostly caused by pre-conditioning chemotherapy. The TERTiNT infusion was well tolerated, and dose-limiting toxicities were not observed. None of the patients showed objective responses. Seven patients (30.4%) achieved stable disease with a median progression-free survival of 3.9 months (range, 3.2-11.3). At the highest dose level (16 × 108 cells/m2), four of five patients showed disease stabilization.The generation of TERTiNTs was feasible and safe and provided an interesting disease control rate in heavily pre-treated cancer patients.Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.