Phase 1 trial of 4-1BB-based adoptive T-cell therapy targeting human telomerase reverse transcriptase in patients with advanced refractory solid tumors
Abstract
Background aims 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.Methods 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 8 cells/m 2, 8 × 10 8 cells/m 2 and 16 × 10 8 cells/m 2). Pre-conditioning chemotherapy, including cyclophosphamide alone or in combination with fludarabine, was administered to induce lymphodepletion.Results 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 8 cells/m 2), four of five patients showed disease stabilization.Conclusions The generation of TERTiNTs was feasible and safe and provided an interesting disease control rate in heavily pre-treated cancer patients.
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hTERT serves as a tumor-associated antigen, generating peptides that, when presented with class I major histocompatibility molecules, can stimulate cytotoxic T-lymphocytes to attack cancer cells.
“hTERT serves as a tumor-associated antigen, generating peptides that, when presented with class I major histocompatibility molecules, can stimulate cytotoxic T-lymphocytes to attack cancer cells.”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [214]
Several phase I and II clinical trials utilizing TERT-directed vaccines have shown promising results.
“Several phase I and II clinical trials utilizing TERT-directed vaccines have shown promising results [213,214].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [214]
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Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy
Nikolouzakis, T. K., Chrysos, E., Docea, A. O., Fragkiadaki, P., Souglakos, J., Tsiaoussis, J., & Tsatsakis, A. (2024) · Cancers · doi:10.3390/cancers16111995 · Cited by 37 · see citing works
- Authors
- Choi, W., Lee, Y., Choi, B. K., Park, B.-M., Kim, Y. H., Yun, T., Lee, W. J., Yoo, H., Baek, J. Y., Woo, S. M., Lim, M. C., & Kwon, B. S.
- Affiliations
- National Cancer Center (KR)
- Corresponding author
- Kwon, Byoung S.
- ORCID
- Venue
- Cytotherapy
- Publisher
- Elsevier BV
- Published
- 2023-11
- Volume
- 25
- Issue
- 11
- Pages
- 1236-1241
- ISSN
- 1465-3249 (ISSN-L)
- OpenAlex
- W4386158534
- Cited by
- 6
- References
- 29
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cytotherapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Trade, Industry and Energy
- National Cancer Center (NCC-1910360)
- Korea Institute for Advancement of Technology
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- 4-1BB, adoptive T cell therapy, human telomerase reverse transcriptase, refractory solid tumors, lymphocyte depletion, cyclophosphamide, fludarabine, dose escalation, safety and tolerability, stable disease
- MeSH terms
- Humans, Leukocytes, Mononuclear, Neoplasms, CD8-Positive T-Lymphocytes, Telomerase, Cell- and Tissue-Based Therapy
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