Combination immunotherapy with GM-CSF and CTLA-4 blockade for hormone refractory prostate cancer: Balancing the expansion of activated effector and regulatory T cells.
Sub-category: Antibodies
Category: Developmental Therapeutics: Immunotherapy
Meeting: 2007 ASCO Annual Meeting
Abstract No: 3001
Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3001
Author(s): L. Fong, B. Kavanagh, Y. Hou, S. O'Brien, J. Valiente, V. Weinberg, B. I. Rini, E. J. Small
Background: 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. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a bone marrow growth factor for antigen presenting cells, which has also been shown to enhance anti-tumor immune responses.
Methods: A phase I trial in patients with metastatic, hormone refractory prostate cancer (HRPC) was undertaken to combine these immunotherapies. 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, given IV on day 1 of each 28-day cycle × 4 cycles. Patients also received GM-CSF 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.
Results: 24 patients have been treated. Of 6 patients treated on the highest dose level (3 mg/kg ×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 consisted of a grade 3 rash in 1 patient at 1.5 mg/kg, a grade 3 rash and panhypopituitarism in 1 patient at 3.0 mg/kg, and a grade 3 colitis in one patient at 3.0 mg/kg. All events were successfully managed. A dose-response relationship was seen between ipilimumab dose and effector T cell activation. Expansion of circulating CD4+ FoxP3+ regulatory T cells was also seen with treatment.
Conclusions: CTLA-4 blockade combined with GM-CSF treatment induces clinical responses in HRPC. Treatment induces both the expansion of activated effector and regulatory T cells in vivo in cancer patients. Finally, CD4 and CD8 T cell activation, adverse events, and clinical responses appear to be dose-dependant. Supported by NIH SPORE P50 CA89520. |
