Abstract 5365: Prolonged survival of patients with advanced renal cancer responding to multi-peptide vaccine IMA901 after single-dose cyclophosphamide

Medientyp: E-Artikel

Titel: Abstract 5365: Prolonged survival of patients with advanced renal cancer responding to multi-peptide vaccine IMA901 after single-dose cyclophosphamide

Beteiligte: Walter, Steffen; Weinschenk, Toni; Stenzl, Arnulf; Zdrojowy, Romuald; Pluzanska, Anna; Szczylik, Cezary; Staehler, Michael; Brugger, Wolfram; Dietrich, Pierre-Yves; Hilf, Norbert; Schoor, Oliver; Fritsche, Jens; Mahr, Andrea; Mendrzyk, Regina; Maurer, Dominik; Vass, Verona; Trautwein, Claudia; Lewandrowski, Peter; Flohr, Christian; Pohla, Heike; Stanczak, Janusz J.; Bronte, Vincenzo; Mandruzzato, Susanna; Biedermann, Tilo; [...]

Erschienen: American Association for Cancer Research (AACR), 2012

Sprache: Englisch

DOI: 10.1158/1538-7445.am2012-5365

ISSN: 0008-5472; 1538-7445

Schlagwörter: Cancer Research ; Oncology

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Beschreibung: Abstract Translational research and the clinical development of therapeutic cancer vaccines requires stronger scientific rationalization. Here we demonstrate how immune response markers as well as biomarkers defining the immune regulatory environment were utilized as guiding tools from discovery to advanced clinical trials of IMA901, a novel therapeutic vaccine for the treatment of renal cell carcinoma (RCC). IMA901 consists of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human RCC tissue by mass spectrometry, selected using differential transcriptomics and preclinically validated by systematic analysis of immunogenicity with artificial antigen-presenting cells. Two consecutive independent clinical studies in a total of 96 HLA-A*02+ advanced/metastatic RCC patients were conducted. The phase I study revealed that T-cell responses to multiple IMA901 antigens were significantly associated with disease control and negatively associated with the presence of FoxP3+ regulatory T cells (Tregs). The subsequent randomized phase II study demonstrated that pre-treatment with a single low dose of cyclophosphamide (Cy) reduced Treg frequencies and prolonged overall survival (OS) in patients who mounted an immune response to the IMA901 vaccine. Additionally, T-cell responses to multiple IMA901 antigens were again associated with clinical benefit. Furthermore, a comprehensive prognostic and predictive biomarker program was conducted. Among cellular biomarkers, highly significantly elevated levels of myeloid-derived suppressor cells (MDSC), IL-17-/IL-10-secreting T cells and dysfunctional T cells in RCC patients vs. healthy individuals were found. Two MDSC populations (CD14+ HLA-DR- and CD14- CD11b+ CD15+) were significantly negatively associated with survival in vaccinated RCC patients. Interestingly, both MDSC populations were also found to be negatively associated with OS in an independent trial in colorectal cancer patients (N=79) implying a broader role for these MDSC species. Additionally, among over 300 serum biomarkers tested, apolipoprotein A-I (ApoA1) and the chemokine CCL17 were found to be predictive for both immune responses to IMA901 and survival of the RCC patients. The knowledge acquired in these trials was used to design a randomized phase III study. In this ongoing study, IMA901 is combined with the tyrosine kinase inhibitor sunitinib based on the findings that sunitinib downmodulates the two MDSC populations described above. Furthermore, in this phase III study, the relevance of ApoA1/CCL17 will be explored by prospectively defined subgroup analyses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5365. doi:1538-7445.AM2012-5365

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