Abstract 5588: T cell activation in relation to clinical responsiveness in patients with metastatic hormone-refractory prostate cancer receiving combined Prostate GVAX and anti-CTLA4 immunotherapy
Authors: Santegoets Saskia J. , Stam Anita G. , Scheper Rik J. , Scholten Petra E. , von Blomberg B M. , Gall Helen , Jooss Karin , Sacks Nathalie , Harding Tom , Hege Kristen , Lowy Israel , van den Eertwegh Alfons J. , Gerritsen Winald R. , de Gruijl Tanja D. 
Published: February 2011

Abstract
The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). Patients received a 500 million cell GVAX priming dose on day 1 followed by 12 bi-weekly intradermal administrations of 300 million cells, while Ipilimumab was administered every 4 wks from day 1 for a total of 6 times. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was clinically active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3-5 mg/kg Ipilimumab doses and PSA stabilizations (Stable Disease, SD) were observed in 1/3 pts in lower (0.3 and 1 mg/kg), and in 7/22 in the higher (3-5 mg/kg) dose levels.
Phenotypic and functional (anti-tumor) effector T cell activation was monitored to identify changes that might predict or correlate with clinical efficacy. Most notably, pronounced and significant increases in frequencies of activated and effector CD4+ and CD8+ T cells were observed by HLA-DR and ICOS expression upon administration of high (3 and 5 mg/kg) but not of low (0.3 and 1 mg/kg) Ipilimumab doses. We also observed a significant increase of CTLA4 and PD-1 expression on CD4+ T cells compared to pre-treatment values in the 3 mg/kg Ipilimumab-administered patients. The latter might be indicative of the induction of concomitant negative feedback signaling. As an indiciation of Tumor-Associated Antigen (TAA) specific responsiveness we tested HLA-Tetramer (Tm) reactivity to NY-ESO and PSMA in HLA-A2 or -A3 positive patients. For NY-ESO, GVAX/Ipi-induced increased seroreactivity (by Western Blot or ELISA) was observed in 6/28 patients. Of these 6 patients, three could be tested for Tm reactivity and in two (1SD, 1 Progressive Disease, PD) increased NY-ESO157 rates were found concomitant with increasing serum Ab levels, whereas no Tm reactivity was detected in 8 patients without seroconversions. Whereas PSMA seroconversions were observed in a total of 12/28 patients (and of note, in 4/5 PR), no Tm positivity at any time was found in a total of 15 patients tested. Further functional Treg and CTL analyses are ongoing. So far, only early HLA-DR upregulation on CD4+ or CD8+ T cells (visit 1 versus visit 3) showed any value for response prediction, since it was observed to significant levels in patients with PR or SD, but not in patients with PD.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5588.