Ellingsen et al. Journal of Translational Medicine (2022) 20:419 https://doi.org/10.1186/s12967-022-03624-z RESEARCH Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination Espen Basmo Ellingsen1,2,3* , Gergana Bounova4, Iliana Kerzeli5, Irantzu Anzar6, Donjete Simnica7, Elin Aamdal8, Tormod Guren8, Trevor Clancy6, Artur Mezheyeuski9, Else Marit Inderberg10, Sara M. Mangsbo5,11, Mascha Binder7, Eivind Hovig1,12 and Gustav Gaudernack3 Abstract Background: This clinical trial evaluated a novel telomerase-targeting therapeutic cancer vaccine, UV1, in combina- tion 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 meta- static 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:// clini caltr ials. gov/ ct2/ show/ NCT02 275416? term= uv1& draw= 2& rank=6 Keywords: Cancer, Immunotherapy, Therapeutic Cancer Vaccine, Telomerase, hTERT, Melanoma, Ipilimumab © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.