Abstract 2934: Increased type-2 T cell rates and coincidence of Th17 spikes with autoimmune events and PSA declines upon combined prostate GVAX and anti-CTLA4 immunotherapy

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). All patients received a 500 million cell priming dose of GVAX on day 1 followed by bi-weekly intradermal treatments of 300 million cells over a 24-week period. Ipilimumab was administered every 4 wks from day 1 during the same period. 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 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 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 pts in lower (0.3 and 1 mg/kg), and in 7 of 22 in the higher (3-5 mg/kg) dose levels. In this study, cytokine profiles of peripheral blood-derived T cells were determined ex vivo and after in vitro stimulation with PMA and ionomycin by intracellular staining for IL-2, −4, −5, −10, TNF-α, IFN-γ and IL-17A. Of these cytokines, only IL-4 was detectable ex vivo in CD4+ and CD8+ T cells; post-treatment increases were detectable in the higher (3-5 mg/kg) but not in the lower (0.3-1 mg/kg) Ipilimumab dose levels. After PMA/ionomycin stimulation, no consistent changes were observed in the frequencies of IFN-γ, IL-2 and TNF-α-producing type-1 T cells compared to pre-treatment values. In contrast, significantly increased rates of IL-4 and IL-5 producing CD4+ and CD8+ T cells were found upon treatment (visit 1 versus visit 5) at higher (3-5 mg/kg) Ipilimumab dose levels. Overall these data clearly demonstrate a shift in favor of a Type-2 cytokine profile due to the GVAX/Ipilimumab administration. The frequencies of IL-17A producing CD4+ T (Th17) cells increased over the course of treatment in 5 of 18 patients. Of note, in 3 (PR) out of 5 of these patients this increase of the Th17 subset coincided with onset of hypophysitis and/or adrenal insufficiencies, as well as the onset of PSA decline. The two patients with increased Th17 rates without these pituitary or adrenal-related ABE showed SD. In summary, our results show that combined GVAX/Ipilimumab administration gives rise to Type-2/Th17 cytokine profiles in mHRPC patients, but that only increases in Th17 show a relation to ABE and PSA responses. 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 2934.</jats:p

Abstract 1229: Pre-existing NY-ESO-1-specific T cell reactivity is associated with improved clinical outcome in castration resistant prostate cancer patients treated with Prostate GVAX and ipilimumab.

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 castration resistant prostate cancer (van den Eertwegh et al, Lancet Oncology, 13: 509-17 2012). The GVAX and ipilimumab combination treatment led to PSA declines of more than 50% (Partial Response, PR) in 5 of 28 patients, PSA stabilizations (Stable Disease, SD) in 12 of 28 patients and disease progression (PD) in 11 of 28 patients. Regressing bone and lymph node metastases were observed in 2/5 PR patients. As an indication of tumor antigen-specific responsiveness we analyzed serologic and T cell responses against NY-ESO-1 before, during and after treatment. NY-ESO-1 seroreactivity (determined by ELISA) was observed in seven of 28 patients (25%). Five patients were seropositive at baseline and 2 became seropositive following treatment; no significant correlations were found with clinical benefit or survival. NY-ESO-1 T cell reactivity was determined in 19 patients by IFNγ ELISPOT after stimulation with a peptide pool of overlapping 20-mer peptides covering the immunodominant region aa121-180. NY-ESO-1-specific T cell responses were detected in 13 of 19 patients (68%) at any time before or during treatment. Increases in the frequency of NY-ESO-1 specific T cells following treatment were only observed in five of these (26%). A remarkably high number of nine out of 19 patients (47%) already exhibited NY-ESO-1-specific T cell reactivity before treatment. Interestingly, three of four (75%) PR patients displayed pre-existing frequencies of NY-ESO-1 T cells, whereas these cells were only detected in six of 15 SD/PD (40%) patients. Moreover, patients with pre-existing NY-ESO-1 T cell reactivity demonstrated a significantly prolonged overall survival (p=0.044, log-rank test). These data suggest that baseline NY-ESO-1 T cell reactivity may have predictive value for the clinical outcome of prostate GVAX and/or ipilimumab treatment. Citation Format: Anita GM Stam, Saskia JAM Santegoets, Alfons JM van den Eertwegh, Rik J. Scheper, Sinéad M. Lougheed, Helen Gall, Karin Jooss, Natalie Sacks, Thomas Harding, Kristen Hege, Israel Lowy, Sacha Gnjatic, Jedd D. Wolchok, Winald R. Gerritsen, Tanja D. de Gruijl. Pre-existing NY-ESO-1-specific T cell reactivity is associated with improved clinical outcome in castration resistant prostate cancer patients treated with Prostate GVAX and ipilimumab. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2013-1229</jats:p