Center for Clinical Trials, National Cancer Center, Goyang, Republic of Korea; Center for Rare Cancers, National Cancer Center, Goyang, Republic of Korea.
Center for Clinical Trials, National Cancer Center, Goyang, Republic of Korea; Center for Lung Cancer, National Cancer Center, Goyang, Republic of Korea.
Cytotherapy. 2023 Nov;25(11):1236-1241. doi: 10.1016/j.jcyt.2023.07.006. Epub 2023 Aug 25.
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 × 10 cells/m, 8 × 10 cells/m and 16 × 10 cells/m). 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 × 10 cells/m), 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.
人类端粒酶逆转录酶（hTERT）是癌症治疗的一个有吸引力的靶点。我们使用来自实体瘤患者的外周血单个核细胞（PBMC）开发了一种有效产生 hTERT 特异性 CD8 T 细胞（hTERT 诱导的天然 T 细胞[TERTiNTs]）的方法，并研究了其可行性和安全性。
这是一项单中心 1 期试验，采用 3+3 剂量递增设计来评估 6 个 TERTiNTs 剂量水平。使用 hTERT 肽谱筛选每位患者的 PBMC，以选择刺激 CD8 T 细胞的肽。从对标准治疗不耐受或难治的患者中产生自体 CD8 T 细胞，使用四种最具刺激性的肽。符合条件的患者接受不同剂量水平（4×10 个细胞/m、8×10 个细胞/m 和 16×10 个细胞/m）的单次静脉输注 TERTiNTs。采用环磷酰胺单独或联合氟达拉滨进行预处理化疗，以诱导淋巴细胞耗竭。
从 2014 年 1 月至 2019 年 10 月，共纳入 24 名患者，中位治疗线数为 3 线。最常见的不良事件是淋巴细胞减少症（79.2%）、恶心（58.3%）和中性粒细胞减少症（54.2%），主要由预处理化疗引起。TERTiNT 输注耐受良好，未观察到剂量限制性毒性。没有患者出现客观反应。7 名患者（30.4%）病情稳定，中位无进展生存期为 3.9 个月（范围为 3.2-11.3）。在最高剂量水平（16×10 个细胞/m），5 名患者中的 4 名病情稳定。
TERTiNTs 的产生是可行和安全的，在接受过多线治疗的癌症患者中提供了有趣的疾病控制率。
