PURPOSE: The progressive immune dysfunctions that occur in advanced melanoma patients make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was performed to test whether immunization with modified HLA-class I tumor peptides in the context of adjuvant therapy results in better immunological responses and improved clinical outcomes in early melanoma patients (stages IIB/C-III). EXPERIMENTAL DESIGN: 43 patients were enrolled to undergo vaccination (n=22) or observation (n=21). The vaccine included four HLA-A*0201-restricted modified peptides (Melan-A/MART-1[27L], gp100[210M], NY-ESO-1[165V], and Survivin[97M]) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m2) and low dose IL-2 (3×106 IU). The immune responses were monitored using ex vivo IFNγ-ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays. RESULTS: Vaccination induced a rapid and persistent increase in specific effector memory CD8+ T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared to the observation group. An extensive immunological analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most important, a limited ability to react to melanoma cells. CONCLUSIONS: Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8+ T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest to reconsider this immunization strategy, particularly in early disease.

Filipazzi, P., Pilla, L., Mariani, L., Patuzzo, R., Castelli, C., Camisaschi, C., et al. (2012). Limited Induction of Tumor-cross-reactive T Cells without a Measurable Clinical Benefit in Early Melanoma Patients Vaccinated with Human Leukocyte Antigen-Class I-Modified Peptides. CLINICAL CANCER RESEARCH, 18(23), 6485-6496 [10.1158/1078-0432.CCR-12-1516].

Limited Induction of Tumor-cross-reactive T Cells without a Measurable Clinical Benefit in Early Melanoma Patients Vaccinated with Human Leukocyte Antigen-Class I-Modified Peptides

VILLA, ANTONELLO;
2012

Abstract

PURPOSE: The progressive immune dysfunctions that occur in advanced melanoma patients make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was performed to test whether immunization with modified HLA-class I tumor peptides in the context of adjuvant therapy results in better immunological responses and improved clinical outcomes in early melanoma patients (stages IIB/C-III). EXPERIMENTAL DESIGN: 43 patients were enrolled to undergo vaccination (n=22) or observation (n=21). The vaccine included four HLA-A*0201-restricted modified peptides (Melan-A/MART-1[27L], gp100[210M], NY-ESO-1[165V], and Survivin[97M]) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m2) and low dose IL-2 (3×106 IU). The immune responses were monitored using ex vivo IFNγ-ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays. RESULTS: Vaccination induced a rapid and persistent increase in specific effector memory CD8+ T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared to the observation group. An extensive immunological analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most important, a limited ability to react to melanoma cells. CONCLUSIONS: Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8+ T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest to reconsider this immunization strategy, particularly in early disease.
Articolo in rivista - Articolo scientifico
tumor recognition
English
2012
18
23
6485
6496
none
Filipazzi, P., Pilla, L., Mariani, L., Patuzzo, R., Castelli, C., Camisaschi, C., et al. (2012). Limited Induction of Tumor-cross-reactive T Cells without a Measurable Clinical Benefit in Early Melanoma Patients Vaccinated with Human Leukocyte Antigen-Class I-Modified Peptides. CLINICAL CANCER RESEARCH, 18(23), 6485-6496 [10.1158/1078-0432.CCR-12-1516].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/39159
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