In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5516-5516
Abstract:
Background: Survivin is a promising tumor-associated antigen for cancer immunotherapy that fulfills two major criteria for this purpose: (1) tumor cells depend on the actions of survivin (inhibition of apoptosis, unrestricted proliferation and angiogenesis); and (2) the protein has demonstrated immunogenicity in patients with different cancers. Here we report results of a first-in-man Phase I study with EMD640744, a cocktail of survivin-derived partially modified HLA class I-restricted peptides in Montanide® ISA 51 VG. Methods: This multicenter, open-label, parallel group, randomized study compared the immunologic efficacy, safety, tolerability and clinical activity of three dosages of EMD640744 (30, 100, or 300 µg) in patients with different types of metastatic or locally advanced solid tumors who were positive for at least one relevant HLA antigen (A1, A2, A3, A24, B7). Patients received weekly s.c. injections of EMD640744 for 8 weeks followed by injections every 4 weeks until tumor progression. For the assessment of the primary endpoint, PBMC samples were prepared at baseline and after 4, 8, 12, 16, and 17 weeks. Peptide-specific T cell responses were analyzed by IFN-γ ELISpot. As a secondary analysis, peptide/HLA-multimer staining was performed. Frequencies of CD8+ T cells specific for patient-relevant single HLA-restricted peptides and EMD640744 were determined ex vivo and after short-term in vitro presensitization with EMD640744. Native homologues of modified vaccination peptides were also included in the analysis. Results: Of 66 patients screened, 53 were treated, and a majority was eligible for response analysis: 38 patients were analyzed by ELISpot and 42 by multimers, with positive ex vivo responses observed in 7 (18%) and 14 (33%) patients, respectively. Combining ex vivo data with results after in vitro stimulation, T cell responses were detected in 14 (37%) and 31 (74%) patients by ELISpot and multimer analysis, respectively. Multimer staining revealed a de novo induction of T cells against survivin peptides in at least 16 patients (38%) whereas pre-existent responses were seen in only 4 patients (10%). T cell responses were detected in all dose groups with similar frequencies. Five out of 10 HLA-A2+ patients reacting against the modified A2-binding peptide in ELISpot assays showed responses against its native homologue. The best tumor response according to RECIST was stable disease in 28% of patients. The most frequent treatment-related adverse events (AEs) were Grade 1-2 local injection site reactions and 2 patients experienced treatment-related Grade 3 AEs (granuloma at injection site and thrombosis). Conclusion: Vaccination with EMD640744 was safe and well tolerated and elicited de novo T cell responses against survivin peptides, demonstrating immunological efficacy of EMD640744 in cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5516. doi:10.1158/1538-7445.AM2011-5516
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-5516
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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