A phase I trial of combination immunotherapy with CTLA-4 blockade and GM-CSF in hormone-refractory prostate cancer

Abstract

2508 Background: CTLA-4 is an costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA-4 blockade with antibody treatment augments T cell responses and anti-tumor immunity in animal models. Clinical trials with anti-CTLA-4 antibody treatment have demonstrated clinical responses in different malignancies including melanoma and hormone-refractory prostate cancer (HRPC). We have also shown that administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) can also induce PSA declines in HRPC patients, presumably through enhancing presentation of endogenous antigens. The current study examines whether combining systemic GM-CSF to CTLA-4 blockade can augment immune and/or clinical responses in HRPC patients. Methods: In a phase I trial of patients with metastatic HRPC, sequential cohorts of 3–6 patients received GM-CSF (sargramostim, Berlex) 250 mg/m2/d SC on days 1–14 of a 28-day cycle with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab (MDX-010), a fully human anti-CTLA antibody (Medarex/BMS), given IV on day 1 of each cycle x 4 cycles. Patients were monitored for toxicity as well as for T cell activation. PSA and radiographic tests were performed at baseline and through therapy to evaluate for clinical response. Results: 18 patients were accrued. Ipilimumab-related dose-limiting toxicity was limited to one patient with grade 3 rash at the 3 mg/kg priming dose level. Seven patients had <50% declines in their serum PSA levels. A dose response relationship was seen between ipilimumab dose and activation of both CD4 and CD8 T cells in the blood. These effects were increased compared to effects seen with ipilimumab treatment alone in prior studies. Interferon-gamma production and lytic activity were also enhanced in circulating antigen-specific CD8+ T cells by the combination. Conclusions: GM-CSF may enhance T cell activation induced by CTLA-4 blockade. With increasing doses of anti-CTLA-4, both CD4 and CD8 T cell activation can be detected in the blood, consistent with a dose-response relationship. Supported by the UCSF Prostate SPORE NIH P50 CA89520. No significant financial relationships to disclose.