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

Exp Biol Med (Maywood). 2024 Jan 31:249:10021. doi: 10.3389/ebm.2024.10021. eCollection 2024.

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.

Keywords: CD8+ T-cells; TLR agonist; hTERT; phase-1 trial; vaccination.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • CD8-Positive T-Lymphocytes
  • Cancer Vaccines* / adverse effects
  • Humans
  • Male
  • Peptides
  • Prostatic Neoplasms*
  • Receptors, Antigen, T-Cell
  • Telomerase* / genetics
  • Telomerase* / metabolism
  • Vaccination

Substances

  • Telomerase
  • Peptides
  • Cancer Vaccines
  • Receptors, Antigen, T-Cell

Grants and funding

The trial was funded by the Candles Charity [Grant Number 1125834] and sponsored by King’s Health Partners. The authors acknowledge additional financial support from the UK Department of Health and Cancer Research UK via Experimental Cancer Medicine Centre grants to King’s Health Partners and the University of Cambridge/Addenbrooke’s Hospital. These centres also hold National Institute for Health Research Biomedical Research Centre (BRC) awards. In Cambridge [Grant Number #BRC-1215-20014] also supports the Cambridge Clinical Research Centre where study participants were seen. We acknowledge the BRC Immune Monitoring Core Facility team at Guy’s and St Thomas’ NHS Foundation Trust [Grant Number IS-BRC-1215-20006] for flow cytometry facilities and assistance, and the Cancer Research UK King’s Health Partners Centre at King’s College London [Grant Number C604/A25135].