Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination

Abstract

Background This clinical trial evaluated a novel telomerase-targeting therapeutic cancer vaccine, UV1, in combination with ipilimumab, in patients with metastatic melanoma. Translational research was conducted on patient-derived blood and tissue samples with the goal of elucidating the effects of treatment on the T cell receptor repertoire and tumor microenvironment. Methods The trial was an open-label, single-center phase I/IIa study. Eligible patients had unresectable metastatic melanoma. Patients received up to 9 UV1 vaccinations and four ipilimumab infusions. Clinical responses were assessed according to RECIST 1.1. Patients were followed up for progression-free survival (PFS) and overall survival (OS). Whole-exome and RNA sequencing, and multiplex immunofluorescence were performed on the biopsies. T cell receptor (TCR) sequencing was performed on the peripheral blood and tumor tissues. Results Twelve patients were enrolled in the study. Vaccine-specific immune responses were detected in 91% of evaluable patients. Clinical responses were observed in four patients. The mPFS was 6.7 months, and the mOS was 66.3 months. There was no association between baseline tumor mutational burden, neoantigen load, IFN-γ gene signature, tumor-infiltrating lymphocytes, and response to therapy. Tumor telomerase expression was confirmed in all available biopsies. Vaccine-enriched TCR clones were detected in blood and biopsy, and an increase in the tumor IFN-γ gene signature was detected in clinically responding patients. Conclusion Clinical responses were observed irrespective of established predictive biomarkers for checkpoint inhibitor efficacy, indicating an added benefit of the vaccine-induced T cells. The clinical and immunological read-out warrants further investigation of UV1 in combination with checkpoint inhibitors. Trial registration Clinicaltrials.gov identifier: NCT02275416. Registered October 27, 2014. https://clinicaltrials.gov/ct2/show/NCT02275416?term=uv1&draw=2&rank=6

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

“…TERT-based vaccines or immunotherapy have been applied for the treatment of several solid tumors with high rates of specific immune responses and improved tumor microenvironment ( 120 ). When the TERT or telomerase vaccine was in combination with a CTLA4 antibody ipilimumab for patients with metastatic melanoma, significantly improved benefits were observed ( 121 , 122 ). To date, there have been no clinical trials regarding UC patients treated with TERT vaccine yet, which calls for clinical investigations.…”

“…In addition, TERT as a tumor-associated antigen can elicit a TERT-specific cytotoxic T lymphocyte (CTL) response (119,120). In that case, TERT-expressing cancer cells are recognized and killed by CTLs (Figure 4) (120).…”

“…In addition, TERT as a tumor-associated antigen can elicit a TERT-specific cytotoxic T lymphocyte (CTL) response (119,120). In that case, TERT-expressing cancer cells are recognized and killed by CTLs (Figure 4) (120). TERT-based vaccines or immunotherapy have been applied for the treatment of several solid tumors with high rates o f s p e c i fi c i m m u n e r e s p o n s e s a n d i m p r o v e d t u m o r microenvironment (120).…”

Therapeutic cancer vaccination against telomerase: clinical developments in melanoma

“…In that respect, antigens derived from telomerase reverse transcriptase (hTERT) is an attractive option. The hTERT expression pattern in cutaneous melanomas appears ubiquitous and comparatively homogenous within individual tumors (Table 1) [22][23][24]. Telomerase is actively expressed to preserve genome integrity in embryonic stem cells and dividing sperm cells, and it is expressed only sparsely in healthy somatic tissues [19].…”

“…Efficacy and safety read-out of checkpoint inhibitor and hTERT vaccine trials in melanoma Larkin J et al [43--45] Robert et al [46] and Carlino et al [47] Zakharia et al [51] Aamdal et al [50]Aamdal et al[41] and Ellingsen et al[22] , complete response; mOS, median overall survival; mPFS, median progression-free survival; NA, not available; ORR, objective response rate; PR, partial response; TRAE, treatment-related adverse event.Therapeutic cancer vaccination against telomerase Ellingsen et al…”