Phase I trial of antibody to CTLA-4 (MDX-010) with melanoma peptides/Ifa for resected stages III/IV melanoma
Year: 2003 Printable Version
Abstract No: 2853
Author(s): J. S. Weber, J. Snively, S. Sian, R. Lau, P. Lee, R. Scotland, T. Davis; Univ of Southern California, Los Angeles, CA; Stanford University School of Medicine, Palo Alto, CA; Medarex Inc., Annandale, NJ
Abstract:
MDX-010 is a human antibody that blocks CTLA-4 on activated T cells, increasing antigen-specific T-cell activity. CTLA-4 blockade with MDX-010 induced clinical regressions in patients with stage IV melanoma and prostate carcinoma after a single dose. Nineteen patients with resected stages III/IV melanoma received escalating doses of anti-CTLA-4 intravenously with each injection of a gp100/tyrosinase/MART-1 peptide vaccine with incomplete Freund's adjuvant (IFA).
Cohorts received antibody at 0.3, 1 and 3 mg/kg. Tyrosinase 368-376 (370D), MART-1 26-35 (27L) and gp100 209-217 (210M) peptides were modified to increase HLA binding, and were administered eight times over twelve months at 1 mg/dose/peptide. Median age was 50, with 10 men and 9 women. 17 patients had stage IV, and 2 had stage III resected disease.
Toxicity and immune response (IR) to the vaccine were the principal endpoints, IR was measured by DTH skin testing with peptides, ELISPOT and peptide-tetramer assays. Time to relapse and overall survival were also assessed. Rapidly reversible dose limiting toxicity was seen at the highest antibody dose of 3 mg/kg. Three patients experienced self-limited grade III diarrhea or abdominal pain associated with CT evidence of rapidly reversible acute ileitis. Two patients had significant rash. Anti-CTLA-4 had a prolonged half-life and saturating levels (>1mcg/ml) were sustained for at least a month after each dose in all patients. Leukocyte subset data showed that total WBC counts increased modestly from 6250/mm3 to 7785/mm3 after one month of treatment in the highest cohorts. There were no consistent effects on activated CD8, CD4 or NK cells, and no difference in CD4/8 ratios with treatment. DTH testing indicated that 4/9 patients responded to gp100, and 2/9 to MART-1. ELISPOT assays showed immune responses in 4/16 patients using fresh CD8 T cells.
All patients are alive, but 5/19 have relapsed, three alive with disease, and two in remission after further surgery. Correlations of IR, toxicity and outcome with dose are ongoing. MDX-010 is immunologically active and alters tolerance. Further characterization of its clinical potential is ongoing. |
