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

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 regulator...

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Published in:Experimental biology and medicine (Maywood, N.J.) N.J.), 2024, Vol.249, p.10021-10021
Main Authors: 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
Format: Article
Language:English
Subjects:
Cancer Vaccines - adverse effects
CD8-Positive T-Lymphocytes
Humans
Male
Peptides
Prostatic Neoplasms
Receptors, Antigen, T-Cell
Telomerase - genetics
Telomerase - metabolism
Vaccination
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Summary: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 9 weeks, with no complete or partial responses, but 24% remained progression-free for ≥6 months. Immunophenotyping showed post-vaccination expansion of CD4 and CD8 T cells with effector phenotypes. The 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.
ISSN:1535-3699
1535-3699
DOI:10.3389/ebm.2024.10021