First-in-human trial focusing on the immunologic effects of the survivin-derived multiepitope vaccine EMD640744.

Abstract

2515 Background: Survivin is a promising antigen for cancer immunotherapy based on two major criteria: tumor cells depend on its actions, and it has demonstrated immunogenicity in patients with different cancers. Here we report immunomonitoring results of a first-in-man Phase I study (EMR 200032-001) with EMD640744, a cocktail of survivin-derived partially modified HLA class I-restricted peptides in Montanide ISA 51 VG. This multicenter, open-label, parallel group, randomized study compared the immunologic efficacy, safety, tolerability and clinical activity of 3 dosages of sc EMD640744 (30, 100 or 300 µg) in patients with different types of metastatic or locally advanced solid tumors positive for at least one relevant HLA antigen (A1, A2, A3, A24, B7). Methods: Routine immunomonitoring to analyze peptide-specific T cell responses at baseline and at weeks 4, 8, 12, 16, and 17 was performed by IFN-γ ELISpot and peptide/HLA-multimer staining (primary endpoint). Additional analyses were performed by intracellular cytokine staining (ICS) to IL-2, IFNγ, TNFα and degranulation marker CD107a after a single in vitro presensitization for 2 weeks with EMD640744. Results: Routine monitoring displayed T cell responses against the vaccine in 14 of 38 patients (37%) assessed by IFNγ-ELISpot and in 31 of 42 patients (74%) by HLA-multimer staining; 16 responses (38%) were clearly de novo induced. ICS revealed 3 relevant findings: 1) 15 of 22 (68%) analyzed patients showed vaccine-specific CD4+ T cells that could be blocked by anti-HLA-Class II antibodies; 2) survivin-specific CD8+ and CD4+ specific T cells often were polyfunctional, responding with degranulation and production of one or more cytokines; and 3) CD8+ responses against native homologues of modified vaccination peptides were demonstrated in 12 of 13 analyzed patients, and CD4+ responses in 5 of 9 patients. Dose dependency was not observed. Conclusions: Vaccination with EMD640744 elicited de novo T cell responses against survivin peptides in many patients, demonstrating immunological efficacy of EMD640744. The capability of EMD640744 to promote CD4-specific T cell help might explain the remarkable number of successfully induced immune responses.