Abstract 4689: Anti-proliferative effect and tumor targeting properties of SurVaxM-derived monoclonal antibodies

Abstract

Abstract Background: Survivin is an inhibitor of apoptosis protein (IAP) which is upregulated in many cancers. SurVaxM (active anti-survivin immunotherapy) is currently being evaluated in a multi-center phase II clinical trial. Circulating anti-survivin antibodies were recently detected in recurrent glioblastoma patients who received SurVaxM immunizations in a previous phase I study. Though primarily functioning as an intracellular molecule, survivin has also been identified in patient serum, and, recently, in tumor-derived exosomes. Methods: Patients in the completed SurVaxM phase I clinical trial produced both antibody and CD8+ T cell responses against survivin. In order to gauge whether antibodies to the vaccine provided any therapeutic benefit, or might serve as potential biomarkers for SurVaxM responsiveness, we tested these antibodies in pre-clinical tumor models. Murine hybridomas derived from the SurVaxM peptide were established and purified yielding several high-affinity IgG antibodies. These antibodies were characterized for target recognition and therapeutic potential. Results: Two of the clones with the highest affinities, 2C2 (IgG2a) and H30 (IgG1), recognized both SurVaxM peptide and the wild type survivin counterpart (ELISA assay), as well as endogenous, full-length survivin (western blotting). Survivin was detected on cells with these antibodies using both immunofluorescence and flow cytometry. Following s.c. implantation of glioblastoma (GL261) and melanoma (B16) tumors in immuno-competent C57BL/6 mice, administration of 2C2 and H30 antibodies (i.p. injection) reduced tumor growth in both models compared to an irrelevant IgG. An orthotopic intracranial glioma study showed similar anti-tumor effects when treated with SurVaxM-derived antibodies. Tumor growth was also inhibited in immuno-compromised (nude) animals treated with 2C2 or H30 antibodies, although to a lesser extent. Conclusions: Antibodies generated in response to the SurVaxM vaccination are highly cross-reactive to survivin and provide therapeutic benefit in immuno-competent mouse tumor models. These antibodies retain some efficacy in immuno-compromised models, indicative of a direct T-cell independent effect. An anti-tumor response through anti-survivin targeted antibodies is unexpected as surface-accessible survivin expression has not yet been well described in the literature. Data presented here highlight possible avenues for investigation of mechanism(s) of action. Citation Format: Michael J. Ciesielski, Sheila Figel, Laura Wiltsie, Phillip Galbo, Cheryl Frank, Robert A. Fenstermaker. Anti-proliferative effect and tumor targeting properties of SurVaxM-derived monoclonal antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4689. doi:10.1158/1538-7445.AM2017-4689