Somatic gene mutations predict outcome of patients receiving adjuvant active specific immunotherapy after resection of stage IV melanoma

Abstract

7522 Background: Cyoreductive surgery plus adjuvant active specific immunotherapy can improve prognosis in stage IV melanoma, if patients are carefully selected. Chemokine receptor 5 (CCR5) is involved in T-cell immunity and dendritic cell activation. Interleukin-10 (IL-10) is immunosuppressive in melanoma. We hypothesized that a somatic CCR5 gene mutation (delta) 32 bp deletion, in conjunction with increasing CD14-derived IL-10 might reflect an unfavorable immune response and ultimately a poorer survival after complete resection and postoperative immunotherapy for stage IV melanoma. Methods: Stage IV melanoma patients enrolled for at least 6 months in phase II trials of Canvaxin specific active immunotherapy (CancerVax Corp, Carlsbad, CA) after complete resection were randomly identified. Genomic DNA extracted from peripheral blood monocytes (PBM) was screened for CCR5 mutation; PCR product size and sequencing verified mutations. Double-staining flow cytometry of serial PBM specimens determined IL-10 levels from CD14+ monocytes. Statistical tests were log-rank, chi-square and student’s T-test. Results: Of the 91 patients, 53 (58%) were men. Median age was 47 years (range, 19–82). Twenty-eight (31%) patients had M1a, 22 (24%) M1b, and 41 (45%) had M1c metastases. Seventy-four (81%) patients had wild-type (Wt) CCR5 gene, 13 (14%) had heterozygous (HtM) CCR5 mutation, and 4(5%) had homozygous (HoM) mutation. At a median follow-up of 38 months, 5-year survival was significantly (p=0.031) higher with Wt CCR5 than HtM/HoM CCR5 (55.6±6.1% vs. 21.4±10.8%). Increasing IL-10 levels (n=10) combined with CCR5 mutation decreased median survival to 9 months and eliminated 5-year survival; by contrast, Wt CCR5 plus decreasing IL-10 was associated with 5-year survival of 76±5% (p<0.0001). Multivariate analyses confirmed the prognostic superiority of CCR5 mutation and IL-10 level vs. age, gender or M stage. Conclusions: Somatic mutations of CCR5 and increasing expression of CD14-derived IL-10 were correlated with poor outcome in stage IV melanoma. These somatic-derived gene products might be used to identify patients for active specific immunotherapy or other treatments. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CancerVax CancerVax