Abstract 2538: Dendritic and T cell functions in patients with metastatic hormone-refractory prostate cancer treated with GVAX immunotherapy for prostate cancer and ipilimumab
Authors: Saskia J.A.M. Santegoets, Alfons J.M. van den Eertwegh, Sinead M. Lougheed, Anita G.M. Stam, Helen Gall, Petra E.T. Scholten, Mary B.E. von Blomberg, Erik Hooijberg, Karin Jooss, Nathalie Sacks, Minh Nguyen, Thomas Harding, Thomas Harding, Kristen Hege, Israel Lowy, Winald R. Gerritsen, Rik J. Scheper, Tanja D. de Gruijl
Journal: Cancer Research (2008)

Abstract The effects of a combination of two allogeneic, GM-CSF-secreting prostate cancer cell lines (GVAX Immunotherapy for Prostate Cancer, Cell Genesys, Inc.) and escalating doses of the anti-CTLA4 antibody ipilimumab (MDX-010, Medarex, Inc.) are currently being evaluated in a Phase I trial of patients with metastatic, hormone-refractory prostate cancer (HRPC). The anticipated synergy of these two novel therapies may potentially lead to augmented T cell-mediated anti-tumor immunity via improved dendritic cell (DC) functions and blockade of inhibitory feedback loops in activated tumor-specific T cells. All patients received a 500 million cell prime dose of the cellular immunotherapy on day 1 followed by bi-weekly intradermal administrations of 300 million cells for a 24-week period. Ipilimumab was administered every 4 wks from day 1 during the same period. Patients were enrolled in cohorts of 3; each cohort was assigned an escalating dose of ipilimumab at 0.3, 1, 3 or 5 mg/kg. Results showed PSA declines of &amp;gt;50% in 5/6 patients at the two highest dose levels of anti-CTLA-4, as well as resolution of multiple lesions on bone scan in two patients, and resolution of abdominal lymph node disease by CT scan and improvement in bone pain in one patient each. T cell activation was monitored to identify changes that correlate with clinical efficacy. Preliminary DC and T cell data are encouraging. Pre-treatment frequencies of circulating myeloid DC (MDC) subsets were significantly reduced in the enrolled HRPC patients, as compared to age- and sex-matched healthy controls. A transient increase in MDC frequencies was observed at the lowest ipilimumab dose level (0.3 mg/kg), but not at the two highest dose levels. The latter may be explained by an observed massive recruitment of MDC to the immunotherapy injection sites. Evidence of transient activation of circulating MDC, concomitant increases of the activation marker HLA-DR on circulating T cells and increased frequencies of circulating memory/effector T cells was found during treatment at the higher ipilimumab dose levels. The transient activation of circulating MDC and T cells showed a reverse kinetics with serum PSA levels. Furthermore, intense skin reactions were observed in response to administration of the cellular immunotherapy, which is consistent with the observed increases in T cell infiltration and Granzyme B expression in injection site biopsies taken during the treatment course and is suggestive of early immune activation. To increase the chances of detecting tumor-specific T cells, both blood and injection sites are monitored for T cell reactivity. Functional regulatory T cell activity is tested in parallel. These on-going analyses are expected to yield valuable data concerning immune effects achieved by the GVAX/ipilimumab combination.