{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zareian N"],"funding":["National Institute for Health Research (NIHR)"],"pagination":["10021"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10911124"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["249"],"pubmed_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 9 weeks, with no complete or partial responses, but 24% remained progression-free for ≥6 months. Immunophenotyping showed post-vaccination expansion of CD4<sup>+</sup> and CD8<sup>+</sup> T cells with effector phenotypes. The <i>in vitro</i> 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<sup>+</sup> 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":["Experimental biology and medicine (Maywood, N.J.)"],"pubmed_title":["A phase 1 trial of human telomerase reverse transcriptase (hTERT) vaccination combined with therapeutic strategies to control immune-suppressor mechanisms."],"pmcid":["PMC10911124"],"funding_grant_id":["NIHR205044"],"pubmed_authors":["Lobo DN","Spicer J","Eremin J","Kordasti S","Pandha H","Eremin O","Funingana G","Baird R","Verma C","Choy D","Shepherd A","Zareian N","Hargreaves S","Farzaneh F","Moghimi P","Kwatra V"],"additional_accession":[]},"is_claimable":false,"name":"A phase 1 trial of human telomerase reverse transcriptase (hTERT) vaccination combined with therapeutic strategies to control immune-suppressor mechanisms.","description":"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<sup>+</sup> and CD8<sup>+</sup> T cells with effector phenotypes. The <i>in vitro</i> 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<sup>+</sup> 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024","modification":"2026-04-29T14:36:17.401Z","creation":"2025-04-06T00:48:43.019Z"},"accession":"S-EPMC10911124","cross_references":{"pubmed":["38463391"],"doi":["10.3389/ebm.2024.10021"]}}