A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma

Giorgio Parmiani, Lorenzo Pilla, Angelo Corti, Claudio Doglioni, Carolina Cimminiello, Matteo Bellone, Danilo Parolini, Vincenzo Russo, Filippo Capocefalo, Cristina Maccalli

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed ex-vivo using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1β and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1β and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23C, 25C, 25C, 29C months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an ex-vivo T cell response and longterm overall survival. These findings warrant confirmation in a larger group of patients.

Original languageEnglish
Pages (from-to)e963406-1-e963406-6
JournalOncoImmunology
Volume3
Issue number11
DOIs
Publication statusPublished - 2 Nov 2014
Externally publishedYes

Fingerprint

Melanoma
Vaccination
Peptides
Chromogranin A
Vaccines
Therapeutics
T-Lymphocytes
Melanoma-Specific Antigens
Neoplasms
Chills
Clinical Trials, Phase I
HLA-A Antigens
Survival
tumor necrosis factor-alpha, CNGRC fusion protein, human
Tumor Necrosis Factor Receptors
Erythema
Serum
Chemokines
varespladib methyl
Immunotherapy

Keywords

  • anti-vascular target therapy
  • combination therapy
  • inflammatory cytokines
  • melanoma
  • peptide-based vaccines
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

Cite this

A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma. / Parmiani, Giorgio; Pilla, Lorenzo; Corti, Angelo; Doglioni, Claudio; Cimminiello, Carolina; Bellone, Matteo; Parolini, Danilo; Russo, Vincenzo; Capocefalo, Filippo; Maccalli, Cristina.

In: OncoImmunology, Vol. 3, No. 11, 02.11.2014, p. e963406-1-e963406-6.

Research output: Contribution to journalArticle

Parmiani, G, Pilla, L, Corti, A, Doglioni, C, Cimminiello, C, Bellone, M, Parolini, D, Russo, V, Capocefalo, F & Maccalli, C 2014, 'A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma', OncoImmunology, vol. 3, no. 11, pp. e963406-1-e963406-6. https://doi.org/10.4161/21624011.2014.963406
Parmiani, Giorgio ; Pilla, Lorenzo ; Corti, Angelo ; Doglioni, Claudio ; Cimminiello, Carolina ; Bellone, Matteo ; Parolini, Danilo ; Russo, Vincenzo ; Capocefalo, Filippo ; Maccalli, Cristina. / A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma. In: OncoImmunology. 2014 ; Vol. 3, No. 11. pp. e963406-1-e963406-6.
@article{4317b0e58dcc4dd3b7c3ee934b7dd06d,
title = "A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma",
abstract = "Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed ex-vivo using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1β and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1β and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23C, 25C, 25C, 29C months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an ex-vivo T cell response and longterm overall survival. These findings warrant confirmation in a larger group of patients.",
keywords = "anti-vascular target therapy, combination therapy, inflammatory cytokines, melanoma, peptide-based vaccines, T cells",
author = "Giorgio Parmiani and Lorenzo Pilla and Angelo Corti and Claudio Doglioni and Carolina Cimminiello and Matteo Bellone and Danilo Parolini and Vincenzo Russo and Filippo Capocefalo and Cristina Maccalli",
year = "2014",
month = "11",
day = "2",
doi = "10.4161/21624011.2014.963406",
language = "English",
volume = "3",
pages = "e963406--1--e963406--6",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "11",

}

TY - JOUR

T1 - A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma

AU - Parmiani, Giorgio

AU - Pilla, Lorenzo

AU - Corti, Angelo

AU - Doglioni, Claudio

AU - Cimminiello, Carolina

AU - Bellone, Matteo

AU - Parolini, Danilo

AU - Russo, Vincenzo

AU - Capocefalo, Filippo

AU - Maccalli, Cristina

PY - 2014/11/2

Y1 - 2014/11/2

N2 - Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed ex-vivo using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1β and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1β and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23C, 25C, 25C, 29C months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an ex-vivo T cell response and longterm overall survival. These findings warrant confirmation in a larger group of patients.

AB - Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed ex-vivo using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1β and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1β and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23C, 25C, 25C, 29C months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an ex-vivo T cell response and longterm overall survival. These findings warrant confirmation in a larger group of patients.

KW - anti-vascular target therapy

KW - combination therapy

KW - inflammatory cytokines

KW - melanoma

KW - peptide-based vaccines

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=84938614205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938614205&partnerID=8YFLogxK

U2 - 10.4161/21624011.2014.963406

DO - 10.4161/21624011.2014.963406

M3 - Article

AN - SCOPUS:84938614205

VL - 3

SP - e963406-1-e963406-6

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 11

ER -