Therapy with human monoclonal anti-CTLA-4 antibody, CP-675,206, reduces regulatory T cells and IL-10 production in patients with advanced malignant melanoma (MM)

Abstract

7505 Background: T-regulatory (T-reg) cells are CD3+CD4+CD25+ and produce IL-10. Engagement of CTLA-4 on activated T cells with CD80/CD86 on APC diminishes T-cell activation and proliferation via inhibition of IL-2 transcription and production. To block signaling of this repressive pathway, 26 patients (pts) with MM were treated with CP-675,206 in a Multi-dose Phase I/II Trial with the intent of augmenting host T-cell mediated responses against the tumor. Methods: Sixteen pts received monthly infusions of CP-675,206 at 10 mg/kg, and another 10 pts at 15 mg/kg every 3 months; all patients were assessed for objective tumor responses (OR) by WHO criteria. Peripheral blood (PB) was obtained from pts at baseline and day 14 of each course of treatment to determine PB T cells (CD3+) and subsets (CD4, CD8, and CD25) by FACS, IL-2, IL-10, and interferon-gamma production, and proliferation of T cells in response to activation of PB mononuclear cells (PBMC) with anti-CD3. Results: Of the 18 evaluable pts, 5 (3 at the 10 mg/kg and 2 at the 15 mg/kg doses) attained OR, 13 progressed (PD); and 8 were stable (SD) or too early for tumor evaluation. After two months of treatment, OR and SD pts had significant increases in %CD3+CD4+ T cells (48.4% vs 57.6%; p=0.018) and a concomitant decrease in %CD3+CD4+CD25+ T-reg cells (38.9% vs 26.7%; p=0.025) whereas PD pts had a significant increase in %CD3+CD4+ T cells (50.4% vs 55.1%; p<0.05) without a reduction in T-reg cells. PBMC from OR, and not PD, had a significant reduction in the constitutive IL-10 production (11.3 pg/mL vs 2.9 pg/mL; p=0.032). Moreover, the ratio of IL-2/IL-10 production by anti-CD3 activated PBMC of OR, and not PD, pts was significantly higher after 1 cycle of treatment (14.2 vs 29.4; p=0.028), compared to baseline. Conclusions: Multiple doses of CP-675,206 can induce OR in pts with MM. CP-675,206 can also reduce the %CD3+CD4+CD25+ T-reg cells and constitutive IL-10 production, and increase the ratio of IL-2/IL-10 production by anti-CD3 activated PBMC. Collectively, these data suggest that CP-675,206 is biologically active in MM and may improve T-cell mediated immunity in clinical responders. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer