Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multipeptide vaccine for resected stages IIIC and IV melanoma

Abstract

9023 Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma that is associated with immune-related adverse events (IrAEs). Methods: 50 HLA A*0201 positive patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times subcutaneously with Ipilimumab at 3 or 10 mg/kg intravenously every 8 weeks for 12 months, and 25 HLA A *0201 negative patients received Ipilimumab alone at 10 mg/kg. Primary endpoints were toxicity and the achievement of a 40% rate of tolerable IrAEs. Immune responses measured by ELISPOT and tetramer assays, and time to relapse were also assessed. 3 melanoma peptides were administered at 1000 mcg/dose each. Results: Median age was 58, with 44 men and 31 women. 46 patients had stage IV, and 29 had stage IIIC resected disease. 19/75 (25%) patients had grades 3–4 IrAEs that were dose-limiting. No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids. Assays of induction of IL-17 secreting T cells showed a positive association with freedom from relapse (p=0.049). Change in slope of the increase in total lymphocyte count at four weeks was also associated with a trend toward freedom from relapse and development of an IrAE. 27 of 75 patients have relapsed with a median of 23 months of follow-up. 10 were again rendered NED surgically and are alive without disease. 68 patients are alive, 10 with disease. Only 1/19 patients with grade 3/4 IrAE has died of disease, compared to 6/56 without a dose limiting IBE. 23 of 27 relapses occurred without a grade 3/4 IrAE, compared with 15 IrAEs in 48 patients without a relapse. ELISPOT assays showed that patients at 10 mg/kg actually had decreased responsiveness in fresh PBMC to PHA and the CEF (CMV, EBV, FLU) pool of peptides. Conclusions: IrAEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab with or without a peptide vaccine. Increases in IL-17 secreting CD4 T cells and the slope of increase in total lymphocytes over 4 weeks are associated with freedom from relapse. These data support testing the current regimen at 10 mg/kg in a larger randomized trial. [Table: see text]