Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study
Clinical studies based on novel rationales and mechanisms of action of chemotherapy agents and cytokines can contribute to the development of new concepts and strategies of antitumor combination therapies. In previous studies, we investigated the paradoxical immunostimulating effects of some chemoth...
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Frontiers Media S.A.
2020-03-01
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Series: | Frontiers in Oncology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00202/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Francesca Urbani Francesca Urbani Virginia Ferraresi Imerio Capone Iole Macchia Belinda Palermo Carmen Nuzzo Angela Torsello Patrizio Pezzotti Diana Giannarelli Anna Fausta Pozzi Mariano Santaquilani Paolo Roazzi Silvia Bastucci Caterina Catricalà Antonia La Malfa Giuseppe Vercillo Novella Gualtieri Carla Buccione Luciano Castiello Francesco Cognetti Paola Nisticò Filippo Belardelli Federica Moschella Enrico Proietti |
spellingShingle |
Francesca Urbani Francesca Urbani Virginia Ferraresi Imerio Capone Iole Macchia Belinda Palermo Carmen Nuzzo Angela Torsello Patrizio Pezzotti Diana Giannarelli Anna Fausta Pozzi Mariano Santaquilani Paolo Roazzi Silvia Bastucci Caterina Catricalà Antonia La Malfa Giuseppe Vercillo Novella Gualtieri Carla Buccione Luciano Castiello Francesco Cognetti Paola Nisticò Filippo Belardelli Federica Moschella Enrico Proietti Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study Frontiers in Oncology immunotherapy melanoma combination therapy chemotherapy drug repurposing interferon-α |
author_facet |
Francesca Urbani Francesca Urbani Virginia Ferraresi Imerio Capone Iole Macchia Belinda Palermo Carmen Nuzzo Angela Torsello Patrizio Pezzotti Diana Giannarelli Anna Fausta Pozzi Mariano Santaquilani Paolo Roazzi Silvia Bastucci Caterina Catricalà Antonia La Malfa Giuseppe Vercillo Novella Gualtieri Carla Buccione Luciano Castiello Francesco Cognetti Paola Nisticò Filippo Belardelli Federica Moschella Enrico Proietti |
author_sort |
Francesca Urbani |
title |
Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study |
title_short |
Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study |
title_full |
Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study |
title_fullStr |
Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study |
title_full_unstemmed |
Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study |
title_sort |
clinical and immunological outcomes in high-risk resected melanoma patients receiving peptide-based vaccination and interferon alpha, with or without dacarbazine preconditioning: a phase ii study |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2020-03-01 |
description |
Clinical studies based on novel rationales and mechanisms of action of chemotherapy agents and cytokines can contribute to the development of new concepts and strategies of antitumor combination therapies. In previous studies, we investigated the paradoxical immunostimulating effects of some chemotherapeutics and the immunoadjuvant activity of interferon alpha (IFN-α) in preclinical and clinical models, thus unraveling novel rationales and mechanisms of action of chemotherapy agents and cytokines for cancer immunotherapy. Here, we carried out a randomized, phase II clinical trial, in which we analyzed the relapse-free (RFS) and overall survival (OS) of 34 completely resected stage III–IV melanoma patients, treated with peptide-based vaccination (Melan-A/MART-1 and NY-ESO-1) in combination with IFN-α2b, with (arm 2) or without (arm 1) dacarbazine preconditioning. All patients were included in the intention-to-treat analysis. At a median follow-up of 4.5 years (interquartile range, 15.4–81.0 months), the rates of RFS were 52.9 and 35.3% in arms 1 and 2, respectively. The 4.5-year OS rates were 68.8% in arm 1 and 62.7% in arm 2. No significant differences were observed between the two arms for both RFS and OS. Interestingly, the RFS and OS curves remained stable starting from 18 and 42 months, respectively. Grade 3 adverse events occurred in 5.9% of patients, whereas grade 4 events were not observed. Both treatments induced a significant expansion of vaccine-specific CD8+ T cells, with no correlation with the clinical outcome. However, treatment-induced increase of polyfunctionality and of interleukin 2 production by Melan-A–specific CD8+ T cells and expansion/activation of natural killer cells correlated with RFS, being observed only in nonrelapsing patients. Despite the recent availability of different therapeutic options, low-cost, low-toxic therapies with long-lasting clinical effects are still needed in patients with high-risk resected stage III/IV melanoma. The combination of peptide vaccination with IFN-α2b showed a minimal toxicity profile and resulted in encouraging RFS and OS rates, justifying further evaluation in clinical trials, which may include the use of checkpoint inhibitors to further expand the antitumor immune response and the clinical outcome.Clinical Trial Registration:https://www.clinicaltrialsregister.eu/ctr-search/search, identifier: 2008-008211-26 |
topic |
immunotherapy melanoma combination therapy chemotherapy drug repurposing interferon-α |
url |
https://www.frontiersin.org/article/10.3389/fonc.2020.00202/full |
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doaj-2919fa77718b4a1e826eb9785c8485212020-11-25T00:37:42ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-03-011010.3389/fonc.2020.00202504648Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II StudyFrancesca Urbani0Francesca Urbani1Virginia Ferraresi2Imerio Capone3Iole Macchia4Belinda Palermo5Carmen Nuzzo6Angela Torsello7Patrizio Pezzotti8Diana Giannarelli9Anna Fausta Pozzi10Mariano Santaquilani11Paolo Roazzi12Silvia Bastucci13Caterina Catricalà14Antonia La Malfa15Giuseppe Vercillo16Novella Gualtieri17Carla Buccione18Luciano Castiello19Francesco Cognetti20Paola Nisticò21Filippo Belardelli22Federica Moschella23Enrico Proietti24Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyMedical Biotechnology and Translational Medicine, Tor Vergata University, Rome, ItalyDepartment of Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyUnit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, ItalyDepartment of Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, ItalyDepartment of Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, ItalyDepartment of Infectious Disease, Istituto Superiore di Sanità, Rome, ItalyBiostatistical Unit, IRCCS Regina Elena National Cancer Institute, Rome, ItalyHospital Pharmacia, IRCCS Regina Elena National Cancer Institute, Rome, ItalyComputer Control and Management, Istituto Superiore di Sanità, Rome, ItalyHealth Technology Assessement, Istituto Superiore di Sanità, Rome, Italy0Clinical Trial Center, IRCCS Regina Elena National Cancer Institute, Rome, Italy1Oncological Dermatology, San Gallicano Hospital, Rome, ItalyHospital Pharmacia, IRCCS Regina Elena National Cancer Institute, Rome, Italy2Clinical Pathology, IRCCS Regina Elena National Cancer Institute, Rome, ItalyUnit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy3FAST—Istituto Superiore di Sanità, Rome, ItalyDepartment of Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, ItalyUnit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy4Institute of Translational Pharmacology, CNR, Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyClinical studies based on novel rationales and mechanisms of action of chemotherapy agents and cytokines can contribute to the development of new concepts and strategies of antitumor combination therapies. In previous studies, we investigated the paradoxical immunostimulating effects of some chemotherapeutics and the immunoadjuvant activity of interferon alpha (IFN-α) in preclinical and clinical models, thus unraveling novel rationales and mechanisms of action of chemotherapy agents and cytokines for cancer immunotherapy. Here, we carried out a randomized, phase II clinical trial, in which we analyzed the relapse-free (RFS) and overall survival (OS) of 34 completely resected stage III–IV melanoma patients, treated with peptide-based vaccination (Melan-A/MART-1 and NY-ESO-1) in combination with IFN-α2b, with (arm 2) or without (arm 1) dacarbazine preconditioning. All patients were included in the intention-to-treat analysis. At a median follow-up of 4.5 years (interquartile range, 15.4–81.0 months), the rates of RFS were 52.9 and 35.3% in arms 1 and 2, respectively. The 4.5-year OS rates were 68.8% in arm 1 and 62.7% in arm 2. No significant differences were observed between the two arms for both RFS and OS. Interestingly, the RFS and OS curves remained stable starting from 18 and 42 months, respectively. Grade 3 adverse events occurred in 5.9% of patients, whereas grade 4 events were not observed. Both treatments induced a significant expansion of vaccine-specific CD8+ T cells, with no correlation with the clinical outcome. However, treatment-induced increase of polyfunctionality and of interleukin 2 production by Melan-A–specific CD8+ T cells and expansion/activation of natural killer cells correlated with RFS, being observed only in nonrelapsing patients. Despite the recent availability of different therapeutic options, low-cost, low-toxic therapies with long-lasting clinical effects are still needed in patients with high-risk resected stage III/IV melanoma. The combination of peptide vaccination with IFN-α2b showed a minimal toxicity profile and resulted in encouraging RFS and OS rates, justifying further evaluation in clinical trials, which may include the use of checkpoint inhibitors to further expand the antitumor immune response and the clinical outcome.Clinical Trial Registration:https://www.clinicaltrialsregister.eu/ctr-search/search, identifier: 2008-008211-26https://www.frontiersin.org/article/10.3389/fonc.2020.00202/fullimmunotherapymelanomacombination therapychemotherapydrug repurposinginterferon-α |