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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.
Affiliation
  • Zareian N; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Eremin O; Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre, Queen's Medical Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.
  • Pandha H; Department of Microbiology and Cellular Sciences, University of Surrey, Guildford, United Kingdom.
  • Baird R; Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.
  • Kwatra V; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Funingana G; Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.
  • Verma C; Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre, Queen's Medical Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.
  • Choy D; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Hargreaves S; Research Department of Pathology, UCL Cancer Institute, Faculty of Medical Sciences, University College London (UCL), London, United Kingdom.
  • Moghimi P; The Institute of Structural and Molecular Biology (ISMB), Birkbeck, University of London, London, United Kingdom.
  • Shepherd A; The Institute of Structural and Molecular Biology (ISMB), Birkbeck, University of London, London, United Kingdom.
  • Lobo DN; Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre, Queen's Medical Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.
  • Eremin J; MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, Queen's Medical Centre, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
  • Farzaneh F; Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre, Queen's Medical Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.
  • Kordasti S; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Spicer J; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
Exp Biol Med (Maywood) ; 249: 10021, 2024.
Article in En | MEDLINE | ID: mdl-38463391
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+ 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Telomerase / Cancer Vaccines Limits: Humans / Male Language: En Journal: Exp Biol Med (Maywood) Journal subject: BIOLOGIA / FISIOLOGIA / MEDICINA Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Telomerase / Cancer Vaccines Limits: Humans / Male Language: En Journal: Exp Biol Med (Maywood) Journal subject: BIOLOGIA / FISIOLOGIA / MEDICINA Year: 2024 Document type: Article Affiliation country: Country of publication: