Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma

Abstract

Purpose: High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2-restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial.

Patients and methods: In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment.

Results: From 1998 to 2003, 131 patients with HLA-A2-positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at >or= 30 months. Immune studies including assays of CD3-zeta expression and numbers of CD4(+)/CD25(+)/FoxP3(+) regulatory T cells, CD15(+)/CD11b(+)/CD14(-) immature myeloid-derived cells, and CD8(+)gp100 tetramer-positive cells in the blood did not correlate with clinical benefit.

Conclusion: The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

Fig 1

Treatment schema (initial 12-week course). gp100 (210M) was administered in incomplete Freund adjuvant every 3 weeks (weeks 1, 4, 7, and 10) for all three clinical trials. High-dose interleukin-2 (IL-2; 600,000 U/kg every 8 hours) was administered up to 14 times intravenous bolus over 5 days, starting the day after vaccine, on weeks 1 and 3 for trial 1, on weeks 7 and 9 for trial 2, and on weeks 1, 4, 7, and 10 for trial 3 (maximum).

Fig 2

Effects of gp100 (210M) plus high-dose interleukin-2 (IL-2) on immune populations. Peripheral-blood mononuclear cells were obtained before treatment and during week 12 of treatment and assayed by flow cytometry. Responding patients are defined in the Results. Dot plots for data are shown with the mean pre- and post-treatment difference (horizontal line) and 95% CI (vertical line) for both responding and nonresponding patients. Left-column responders are based on PFS, and right-column responders are based on objective response. The results are based on percentage of mononuclear cells. (A) Percentage of CD11b⁺/CD15⁺/CD14⁻ preversus post-treatment expression in responders versus nonresponders by progression-free survival (PFS; P = .5052) or by objective responses (P = .4269). (B) Percentage of CD4⁺/CD25⁺/FoxP3⁺ preversus post-treatment levels in responders versus nonresponders by PFS (P = .6844) or by objective responses (P = .6340). (C) Percentage of CD3-ζ preversus post-treatment levels of expression in responders versus nonresponders by PFS (P = .7522) or by objective responses (P = .1445). (D) Percentage of CD8⁺ T cells expressing gp100-209 tetramers as the log of percentage of CD8⁺ T cells. There is no difference between preversus post-treatment levels of gp100 tetramer–positive cells in responders versus nonresponders by PFS (P = .7839) or by objective responses (P = .1502). (E) CD8⁺ T cells expressing influenza tetramers as the log of percentage of CD8⁺ T cells. There is no difference between pre- and post-treatment levels of flu-positive cells in any of the cohorts.