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 effe...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03624-z |
| _version_ | 1811267711117819904 |
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| author | Espen Basmo Ellingsen Gergana Bounova Iliana Kerzeli Irantzu Anzar Donjete Simnica Elin Aamdal Tormod Guren Trevor Clancy Artur Mezheyeuski Else Marit Inderberg Sara M. Mangsbo Mascha Binder Eivind Hovig Gustav Gaudernack |
| author_facet | Espen Basmo Ellingsen Gergana Bounova Iliana Kerzeli Irantzu Anzar Donjete Simnica Elin Aamdal Tormod Guren Trevor Clancy Artur Mezheyeuski Else Marit Inderberg Sara M. Mangsbo Mascha Binder Eivind Hovig Gustav Gaudernack |
| author_sort | Espen Basmo Ellingsen |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-04-12T21:07:46Z |
| format | Article |
| id | doaj.art-e47b5805c551439fb54758c8276abab0 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-12T21:07:46Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-e47b5805c551439fb54758c8276abab02022-12-22T03:16:40ZengBMCJournal of Translational Medicine1479-58762022-09-0120111310.1186/s12967-022-03624-zCharacterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccinationEspen Basmo Ellingsen0Gergana Bounova1Iliana Kerzeli2Irantzu Anzar3Donjete Simnica4Elin Aamdal5Tormod Guren6Trevor Clancy7Artur Mezheyeuski8Else Marit Inderberg9Sara M. Mangsbo10Mascha Binder11Eivind Hovig12Gustav Gaudernack13Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalENPICOM B.V.Department of Pharmacy, Science for Life Laboratory, Uppsala UniversityNEC OncoimmunityDepartment for Internal Medicine IV - Hematology and Oncology, Universitätsklinikum Halle (Saale)Department of Oncology, Oslo University HospitalDepartment of Oncology, Oslo University HospitalNEC OncoimmunityHistoOne ABDepartment of Cellular Therapy, Oslo University HospitalDepartment of Pharmacy, Science for Life Laboratory, Uppsala UniversityDepartment for Internal Medicine IV - Hematology and Oncology, Universitätsklinikum Halle (Saale)Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalUltimovacs ASAAbstract 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=6https://doi.org/10.1186/s12967-022-03624-zCancerImmunotherapyTherapeutic Cancer VaccineTelomerasehTERTMelanoma |
| spellingShingle | Espen Basmo Ellingsen Gergana Bounova Iliana Kerzeli Irantzu Anzar Donjete Simnica Elin Aamdal Tormod Guren Trevor Clancy Artur Mezheyeuski Else Marit Inderberg Sara M. Mangsbo Mascha Binder Eivind Hovig Gustav Gaudernack Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination Journal of Translational Medicine Cancer Immunotherapy Therapeutic Cancer Vaccine Telomerase hTERT Melanoma |
| title | Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination |
| title_full | Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination |
| title_fullStr | Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination |
| title_full_unstemmed | Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination |
| title_short | Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination |
| title_sort | characterization of the t cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and htert vaccination |
| topic | Cancer Immunotherapy Therapeutic Cancer Vaccine Telomerase hTERT Melanoma |
| url | https://doi.org/10.1186/s12967-022-03624-z |
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