CTLA-4 blockade for hormone refractory prostate cancer: Dose-dependent induction of CD8+ T cell activation and clinical responses
Abstract Number: 2539
Author Block:
Lawrence Fong, Serena Kwek, Brian Kavanagh, Shaun O'Brien, Douglas McNeel, Vivian Weinberg, Brian Rini, Eric J. Small. Univ. of California, San Francisco, San Francisco, CA, University of Wisconsin School of Medicine and Public Health, Madison, WI
CTLA-4 is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment T cell responses and anti-tumor immunity in animal models and is being developed as an immunotherapy for cancer patients. We performed a phase I trial in patients with metastatic, hormone refractory prostate cancer (HRPC) where sequential cohorts of 3-6 patients were treated with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab, a fully human anti-CTLA-4 antibody (Medarex/BMS), given IV on day 1 of each 28-day cycle x 4 cycles. Patients also received GM-CSF (sargramostim, Berlex) 250 mg/m2/d SC on days 1-14 of the 28-day 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. 24 patients have been treated in the initial phase of this study. Of 6 patients treated on the highest dose level (3.0 mg/kg x 4), 3 (50%) had confirmed PSA declines of >50%, and one of these patients had a partial response in hepatic metastases. Immune-related adverse events associated with ipilimumab treatment were also seen more frequently at higher doses of treatment. Expansion of CD25+CD69+ CD8 T cells was also seem primarily at the highest dose level. The treatment also induced an antibody and CD8 T cell immune response to NY-ESO-1. These results demonstrate that CTLA-4 blockade induces not only the expansion of activated effector CD8 T cells in vivo in cancer patients, but also can induce from the endogenous T cell repertoire of these patients T cells that are specific for tumor-associated antigens. CD8 T cell activation, toxicity, and clinical responses also appear to be dose-dependent. Supported by NIH P50 CA89520. |
