Inability to generate activated T effector cells and the presence of strong suppressor mechanisms have limited cancer vaccine efficacy. Human telomerase reverse transcriptase (hTERT) is expressed in > 90% of tumours but is HLA dependent, which has restricted its use to patients with a particular HLA haplotype. We sought to address these problems with a novel vaccination strategy.
Each vaccination was preceded by 10 days of metronomic low dose oral cyclophosphamide, designed to reduce Tregs. A vaccine consisting of 7 hTERT peptides, predicted to bind MHC Class I and II proteins, not HLA restricted, was given 3-weekly ID. Adjuvants (Montanide ID and topical imiquimod), were used to optimise hTERT presentation. The primary objective was safety, with secondary objectives of immunological and clinical efficacy. Blood lymphocyte phenotypic profiles were analysed ex vivo and post culture to identify activated T effector cells, checkpoint-regulatory T cells and Tregs. T cell receptor (TCR) sequencing was performed prior to and post vaccination.
17 patients (pts) have completed treatment. Vaccination was well tolerated, 1 withdrew following an injection site reaction. 4 pts (24%) had stable disease for >6 months (colorectal, lung, pancreas, prostate). Baseline activated T cells in pts (CD8+CTLA-4+, n = 9) were similar to healthy donors (HDs), but increased up to 3-fold post-vaccination (p = 0.017). T cells from 5 pts were cultured in vitro post-vaccination; peptide-specific activation of CD4+ and CD8+ T cells was seen in 4/5 and 3/5, respectively. Baseline checkpoint regulatory (PD-1+) CD4+/CD8+ T cells were 8-10 fold higher in pts (CD4+, p = 0.011; CD8+, p = 0.004) than HDs; post-vaccination levels fell but remained >HDs. Post-treatment Tregs fell significantly (FOXP3+PD-1+, p = 0.016). TCR sequencing demonstrated the emergence of clonally expanded T cells, including hTERT-specific clones.
This pan-tumour generic vaccine was safe, with sustained disease stabilisation in a subset of patients with a range of tumour types. Immune-suppressor T cell numbers fell, and hTERT-specific T effector cells were generated.
Clinical trial identification
Legal entity responsible for the study
King's Health Partners.
All authors have declared no conflicts of interest.