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Oncoimmunology. 2014 Dec 21;3(11):e963406. eCollection 2014 Nov.

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

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Unit of Immuno-biotherapy of Melanoma and Solid Tumors; San Raffaele Foundation Research Institute ; Via Olgettina , Milan.
Unit of Tumor Biology and Vascular Targeting; San Raffaele Foundation Research Institute ; Via Olgettina , Milan.
Unit of Pathology; San Raffaele Foundation Research Institute ; Via Olgettina , Milan.
Unit of Cellular Immunology; San Raffaele Foundation Research Institute ; Via Olgettina , Milan.
Unit of Gastrointestinal Surgery; San Raffaele Foundation Research Institute ; Via Olgettina , Milan.
Unit of Cancer Gene Therapy; San Raffaele Foundation Research Institute ; Via Olgettina , Milan.


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, 23+, 25+, 25+, 29+ 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 long-term overall survival. These findings warrant confirmation in a larger group of patients.


APC, antigen presenting cell; CT, cancer/testis; CgA, chromogranin A; DFS, disease-free survival; MAA, melanoma-associated antigens; MCP-1, macrophage chemoattractant protein 1; MIP-1β, macrophage inflammatory protein 1β; OS, overall survival; PBMC, peripheral blood mononuclear cell; PD, progression of disease; PFS, progression-free survival; RR, response rate; T cells; TNFα, tumor necrosis factor α; anti-vascular target therapy; combination therapy; inflammatory cytokines; melanoma; peptide-based vaccines; sTNFR, soluble tumor necrosis factor receptor

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