Abstract 4399: Immunostimulatory effects of HSP90 inhibition: Insights from combinational immunotherapies targeting EphA2
Authors: Rao Aparna , Kawabe Mayumi , Storkus Walter J. 
Published: August 2012

Abstract
Introduction: Limited MHC Class I antigen presentation by tumor cells has consistently been identified as a significant barrier to cancer immunotherapy. Combinational regimens that coordinately enhance tumor-associated antigen (TAA) presentation on tumor MHC Class I molecules and stimulate TAA-specific T cell immunity are expected to yield synergistic clinical benefit. We have previously shown in vitro that the HSP90 inhibitor 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), which is currently being evaluated as an anti-cancer agent in phase I/II clinical trials, is capable of enhancing MHC Class I presentation of EphA2, a TAA that is over expressed in several cancers (Melanoma, lung cancer, sarcomas). To further characterize the therapeutic potential of this approach, we are currently assessing the safety and effectiveness of a rationally-designed combinational therapy incorporating 17-DMAG and EphA2-targeted immunotherapy in murine tumor models. Results: The anti-tumor efficacy of 17-DMAG was evaluated in an MCA205 sarcoma model applied to syngenic mice.17-DMAG facilitated a dose-dependent reduction in EphA2 expression in vivo, which correlated with increased presentation of EphA2 peptides on tumor MHC class I molecules. Increased EphA2 presentation on tumor MHC class I molecules was determined by documenting the increased recognition of treated tumor cells by EphA2-specific T cells.17-DMAG treatment, when combined with 2 different immunotherapy approaches targeting EphA2 (adoptive transfer of EphA2-specific T cells and DC-based vaccine), led to superior anti-tumor impact and in some cases, even complete tumor regression, compared to single-modality approaches. In addition, combination treatment groups had increased infiltration of tumors by CD4+ and CD8+ T cells and decreased Tregs and Myeloid-derived suppressor cells (MDSCs) compared to groups receiving single mode of treatment or untreated progressors. Infiltrating CD8 T cells in the tumor in the combination therapy cohort were specific for EphA2, as assessed by in vitro stimulation. Skewing of the immune response towards a type 1 phenotype was caused by upregulated inflammatory chemokines and their receptors in the TME. 17-DMAG also facilitated vascular remodeling of the tumor with decreased endothelial cell and pericyte coverage coinciding with increased VCAM-1 expression, which may contribute to the enhanced recruitment of antigen-specific T cells. Conclusions: Our studies suggest that conditionally decreased EphA2 protein levels in tumors treated with 17-DMAG is accompanied by increased recognition by therapeutic anti-EphA2 T cells in vivo. Combinational immunotherapies integrating 17-DMAG have superior anti-tumor efficacy compared to single modality approaches and are orchestrated by the vascular and immunologically-preferred alterations in the tumor promoted by 17-DMAG.
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 4399. doi:1538-7445.AM2012-4399