Abstract 5512: Immune correlates of clinical response and survival in castration-resistant prostate cancer patients treated with prostate GVAX and anti-CTLA4 immunotherapy
Authors: Santegoets Saskia J.A.M. , van den Eertwegh Alfons J.M. , Stam Anita G.M. , Scheper Rik J. , Lougheed Sinéad M. , Scholten Petra E.T. , von Blomberg Mary B.M.E. , Gall Helen , Jooss Karin , Nguyen Minh C. , Harding Tom , Sacks Natalie , Hege Kristen , Lowy Israel , Chin Kevin , Gerritsen Winald R. , de Gruijl Tanja D. 
Published: June 2012

Abstract
The effects of Prostate GVAX and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with castration resistant prostate cancer. Results showed that the GVAX/Ipilimumab combination was clinically active with PSA declines of more than 50% (Partial Response, PR) in 6 and PSA stabilizations (Stable Disease, SD) in 11 of 28 patients. Immune response monitoring was performed to identify changes that might predict or correlate with clinical efficacy.
Upon administration of high Ipilimumab dosages (3 or 5 mg/kg), significant increases in frequencies of activated CD4+ and/or CD8+ T cells were observed by HLA-DR, PD-1, FoxP3 and ICOS expression. Monitoring over the course of treatment, revealed these markers to be differentially associatied with survival, as were levels of effector/memory T cells or Tregs. Early HLA-DR upregulation appeared useful as a marker for response prediction, since it was observed to significant levels in PR or SD, but not in PD patients. In addition, GVAX/Ipilimumab administration was found to induce Th2/Th17 cytokine profiles, as determined ex vivo by intracellular staining of peripheral T cells. Significantly increased levels of IL-4 in both CD4+ and CD8+ T cells were observed in patients with PR or SD, but not in patients with PD and, importantly, profound up-regulation of CD4+IL-5+ T cell frequencies was associated with improved overall survival (p=0.03). Similarly, significantly increased Th17 rates were only observed in patients with PR and SD (p&lt;0.05). Of particular interest, the increased Th17 frequencies coincided with onset of hypophysitis and/or adrenal insufficiencies, as well as of PSA declines in PR patients.
As an indication of tumor-specific responsiveness, IgG antibody responses against 11 (prostate) tumor-associated antigens were determined by western blot and ELISA. Increased seroreactivity to prostate-specific membrane antigen (PSMA), pyridoxamine 5′-phosphate oxidase (PNPO) and/or Neuropilin-2 (NRP2) was significantly correlated with improved overall survival (p&lt;0.03).
Our data indicate that changes in frequencies of activated memory/effector T cells and Tregs, Th2 and Th17 rates and seroconversion to multiple tumor antigens may define a predictive immune profile for patients with potential benefit from Prostate GVAX and/or anti-CTLA4 immunotherapy.
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 5512. doi:10.1158/1538-7445.AM2011-5512