A phase 1 trial of human telomerase reverse transcriptase (hTERT) vaccination combined with therapeutic strategies to control immune-suppressor mechanisms

Zareian, Nahid; Eremin, Oleg; Pandha, Hardev; Baird, Richard; Kwatra, Vineet; Funingana, Gabriel; Verma, Chandan; Choy, Desmond; Hargreaves, Steven; Moghimi, Pejvak; Shepherd, Adrian; Lobo, Dileep N; Eremin, Jennifer; Farzaneh, Farzin; Kordasti, Shahram; Spicer, James

Abstract

The presence of inhibitory immune cells and difficulty in generating activated effector T cells remain obstacles to development of effective cancer vaccines. We designed a vaccine regimen combining human telomerase reverse transcriptase (hTERT) peptides with concomitant therapies targeting regulatory T cells (Tregs) and cyclooxygenase-2 (COX2)-mediated immunosuppression. This Phase 1 trial combined an hTERT-derived 7-peptide library, selected to ensure presentation by both HLA class-I and class-II in 90% of patients, with oral low-dose cyclophosphamide (to modulate Tregs) and the COX2 inhibitor celecoxib. Adjuvants were Montanide and topical TLR-7 agonist, to optimise antigen presentation. The primary objective was determination of the safety and tolerability of this combination therapy, with anti-cancer activity, immune response and detection of antigen-specific T cells as additional endpoints. Twenty-nine patients with advanced solid tumours were treated. All were multiply-pretreated, and the majority had either colorectal or prostate cancer. The most common adverse events were injection-site reactions, fatigue and nausea. Median progression-free survival was 9weeks, with no complete or partial responses, but 24% remained progression-free for ≥6months. Immunophenotyping showed post-vaccination expansion of CD4+ and CD8+ T cells with effector phenotypes. The in vitro re-challenge of T cells with hTERT peptides, TCR sequencing, and TCR similarity index analysis demonstrated the expansion following vaccination of oligoclonal T cells with specificity for hTERT. However, a population of exhausted PD-1+ cytotoxic T cells was also expanded in vaccinated patients. This vaccine combination regimen was safe and associated with antigen-specific immunological responses. Clinical activity could be improved in future by combination with anti-PD1 checkpoint inhibition to address the emergence of an exhausted T cell population.

• Journal Article Type: Article
• Acceptance Date: Jan 4, 2024
• Online Publication Date: Jan 31, 2024
• Publication Date: Jan 31, 2024
• Deposit Date: Jan 5, 2024
• Publicly Available Date: Jan 5, 2024
• Journal: Experimental Biology and Medicine
• Print ISSN: 1535-3702
• Electronic ISSN: 1535-3699
• Publisher: SAGE Publications
• Peer Reviewed: Peer Reviewed
• Volume: 249
• Issue: 1
• DOI: https://doi.org/10.3389/ebm.2024.10021
• Keywords: CD8-Positive T-Lymphocytes, Prostatic Neoplasms, Male, phase-1 trial, CD8+ T-cells, Peptides, Humans, hTERT, Receptors, Antigen, T-Cell, TLR agonist, vaccination, Cancer Vaccines - adverse effects, Telomerase - genetics - metabolism, Vaccination
• Public URL: https://nottingham-repository.worktribe.com/output/29271601
• Publisher URL: https://www.ebm-journal.org/articles/10.3389/ebm.2024.10021/full#h12
• Additional Information: Copyright © 2024 Zareian, Eremin, Pandha, Baird, Kwatra, Funingana, Verma, Choy, Hargreaves, Moghimi, Shepherd, Lobo, Eremin, Farzaneh, Kordasti and Spicer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.