Abstract 1792: Selective class I HDAC inhibitor SNDX-275 enhances anti-tumor survivin vaccine therapy by suppressing regulatory T cells in a model of prostate cancer
Authors: Shen Li , Ciesielski Michael , Ellis Leigh , Fenstermaker Robert , Pili Roberto 
Published: June 2012

Immunotherapy has been recently approved for the treatment of castrate refractory prostate cancer but its clinical benefit is limited. A major barrier in vaccine therapy remains the presence of immunosuppressive factors such as regulatory T cells (Tregs). Tregs are predominant in various cancers including advanced prostate cancer. Studies have shown that tolerance mechanisms can be induced by tumor and surrounding stromal cells or immunotherapy itself. In our laboratory we have observed that SNDX-275, a class I HDAC specific inhibitor can down-regulate Foxp3 expression, suppress Treg function, and enhance the anti-tumor effect of cytokine therapy. Here, we present a current study carried out in a castration-resistant prostate cancer model where we combined SNDX-275 with a novel peptide mimic vaccine (SVN53-67/M57-KLH (SurVaxM)) targeted towards the intracellular tumor associated antigen (TAA) survivin. We hypothesize that combination of SNDX-275 and SurVaxM vaccine will mediate a greater anti-tumor response by inducing an efficient CD8+ cytotoxic T cell response and overcoming Tregs mediated immunosuppressive effect in tumor bearing animals. We have generated and utilized a transplant castrate resistant (CR) PCa murine model. Myc-CaP cell lines derived from the Hi-Myc transgenic prostate cancer mouse model were injected (1×106 cells/mouse) subcutaneously to male FVB Wt mice. Survivin expression has been confirmed in myc tumors. Tumor bearing animals were surgically castrated post tumor establishment and consequent tumors were passaged through 5 additional rounds of surgically castrated Wt FVB male mice. CR tumor bearing mice were randomized into four groups and treated with vehicle, SNDX-275 (5 days/week, 5mg/kg), SurVaxM (1 dose/week) or combination. We demonstrate that treatment with SNDX-275 alone and in combination efficiently reduced Foxp3 expression in Tregs. Following four weeks of treatment, SNDX-275 or SurVaxM single treatment displayed modest anti-tumor effect (10-25% of reduction). Excitingly, combination of SNDX-275 and SurVaxM dramatically reduced tumor weight (∼80% reduction, p=0.002) and inhibited tumor growth rate when compared to either vehicle or single treatment groups. Tumor specific CD8+ T cell response and tumor specific cytotoxicity are being evaluated. This is the first study, to our knowledge, to show that the class I HDAC inhibitor SNDX-275 in combination with a vaccine therapy enhances prostate tumor response by inhibition of immunosuppressive Tregs. These findings suggest that the combination of a class I HDAC inhibitor with vaccine therapy is a rational therapeutic strategy for advanced, castrate refractory prostate cancer.

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 1792. doi:10.1158/1538-7445.AM2011-1792