1. Phase 1 trial of 4-1BB-based adoptive T-cell therapy targeting human telomerase reverse transcriptase in patients with advanced refractory solid tumors.
- Author
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Choi, Wonyoung, Lee, Youngjoo, Choi, Beom K., Park, Bo-Mi, Kim, Young H., Yun, Tak, Lee, Woo Jin, Yoo, Heon, Baek, Ji Yeon, Woo, Sang Myung, Lim, Myeong Cheol, and Kwon, Byoung S.
- Subjects
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TELOMERASE reverse transcriptase , *T cells , *MONONUCLEAR leukocytes - Abstract
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, 3.2โ11.3). 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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