Biochemical and immunologic correlates of clinical response in a combination trial of the GM-CSF-gene transduced allogeneic prostate cancer immunotherapy and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHRPC)

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5120 Background: A Phase 1 trial is underway to study the GM-CSF-secreting immunotherapy for prostate cancer (GVAX immunotherapy [GVAX IT]) and ipilimumab (ipi) in mHRPC patients (pts). Methods: Twelve pts were treated for 24 weeks (wks) with bi-weekly intradermal injections of GVAX IT and monthly Ipi. Pts were enrolled in cohorts of 3; each cohort received an escalating dose of ipi: 0.3, 1, 3 or 5 mg/kg. Results: Median follow-up is 15.0 months. All pts had GVAX IT injection site reactions. Five of six pts at the higher ipi doses (3 and 5 mg/kg) developed Grade 2 or 3 immune-related endocrinopathy, consistent with hypophysitis manifested by adrenal insufficiency and/or hypothyroidism, all successfully treated with standard hormone replacement. Two pts were tapered off Synthroid within 6 months (m). There was no induction of the alpha-21-hydroxylase auto-antibody that is seen in 90% of cases of auto-immune adrenal insufficiency. One pt in the 5 mg group developed a Grade 3 dose-limiting alveolitis. PSA responses (declines > 50%) were seen in 5/6 treated at the two higher ipi doses with median response duration of 4.9 m (2 on-going at 7.2 m and 12.8 m). These PSA responses were associated with immune-related endocrinopathy but were not consistently correlated with declines in adrenal androgens. One pt had resolution of measurable disease on abdominal CT scan. Immunomonitoring studies showed T cell and dendritic cell activation, more pronounced at higher doses. Biopsies of injection sites showed T cell infiltration. Multiple tumor-reactive antibodies (abs) induced by tx were identified by serologic analysis (SEREX), including abs to filamin B. Screening against 20 defined prostate cancer antigens demonstrated induction of abs to PSMA and NY-ESO-1. Conclusions: The GVAX IT and ipilimumab combination is active in mHRPC. There was an association between PSA response and immune-related adverse events. The PSA responses cannot be accounted for by adrenal insufficiency. The relationship between clinical activity and serologic response to identified antigens is under investigation. Tx of 16 additional pts is planned. No significant financial relationships to disclose.