Abstract B20: Immune vs. clinical response monitoring in patients with metastatic hormone-refractory prostate cancer receiving combined 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 Sinead M. , Scholten Petra E.T. , Gall Helen , Jooss Karin , Sacks Natalie , Harding Thomas C. , Hege Kristen , Lowy Israel , Gerritsen Winald R. , de Gruijl Tanja D. 
Published: January 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 dose cohorts, and were associated with Autoimmune Breakthrough Events (ABE), including Grade 2 or 3 hypophysitis and Grade 3 alveolitis. PSA stabilizations (Stable Disease, SD) were observed in 1/3 patients in lower (0.3 and 1 mg/kg), and in 7 of 22 in the higher (3–5 mg/kg) dose levels. Moreover, regressing bone and lymph node metastases were observed in 2/5 PR patients.
Immune response monitoring was performed 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) Ipilimumab doses; a relation to clinical behaviour was only observed for HLA-DR with earlier and more pronounced increases in patients with PR or SD. As an indication of tumor-specific responsiveness HLA-Tetramer (Tm) and seroreactivity to NY-ESO and PSMA were tested. For NY-ESO, therapy-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. PSMA seroconversions were observed in a total of 12/28 patients (and, of note, in 4/5 PR), but no Tm positivity at any time was found in a total of 15 patients tested. In the 3–5 mg/kg dose levels (n=22), PSMA seroconversion was associated with increased overall survival (P=0.062). In addition, combined GVAX/Ipilimumab administration was found to induce Type-2/Th17 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 (P&lt;0.05), but not in patients with PD, while Th17 spikes in 3/5 patients coincided with ABE and PSA responses.
In summary, our analyses so far reveal a relationship between clinical efficacy, PSMA seroconversion, and generalized T cell activation accompanied by Th2 and Th17 skewing. Together these data point to a mechanism of action whereby combined Prostate GVAX and anti-CTLA4 immunotherapy can induce both Th2/humoral and Th17/cell-mediated immune responses, resulting in tumor destruction and collateral autoimmunity. Supported by the Prostate Cancer Foundation and the Dutch Cancer Society (KWF-VU 2006-3697)
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B20