title: Serologic evidence of autoimmunity in E2696 and E1694 patients with high-risk melanoma treated with adjuvant interferon alfa.
abstract: We evaluated Eastern Cooperative Group phase II and III trials E2696 and E1694 to assess the incidence and prognostic significance of autoimmunity induced by adjuvant high-dose interferon-α2b (HDI). In E2696, patients with resectable high-risk melanoma were randomized to receive vaccination with GM2-KLH/QS-1 (GMK) plus concurrent HDI, GMK plus sequential HDI, or GMK alone. E1694 randomized patients to either HDI or GMK. Sera from 103 patients in E2696 and 691 patients in E1694 banked at baseline and up to three subsequent time points were tested by ELISA for the development of five autoantibodies. In E2696, autoantibodies were induced in 16 patients (23.2%; n=69) receiving HDI and GMK and two patients (5.9%; n=34) receiving GMK alone (P=0.031). Of 691 patients in E1694, 67 (19.1%) who received HDI (n=350) developed autoantibodies, but only 16 patients (4.7%) developed autoantibodies in the vaccine group (n=341; P<0.001). Almost all induced autoantibodies were detected at ≥12 weeks after the initiation of therapy. A 1-year landmark analysis among resected stage III patients treated with HDI in E1694 showed a trend toward a survival advantage associated with HDI-induced autoimmunity (hazard ratio=0.80; 95% confidence interval: 0.50-1.98; P=0.33). Therefore, adjuvant HDI therapy is associated with the induction of autoimmunity that should be further investigated prospectively as a surrogate marker of adjuvant therapeutic benefit. This potential biomarker develops over the course of up to 1 year, and cannot be used to alter the course of therapy. Studies of the genetic determinants of this response may better discriminate patients more likely to benefit from HDI immunomodulatory therapy.
authors: aDepartment of Medicine, Clinical and Translational Science Institute, University of Pittsburgh bUniversity of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania cDana-Farber Cancer Institute, Biostatistics and Computational Biology, Boston, Massachusetts, USA.
authors: Ahmad A
authors: AA
authors: Tarhini
authors: Donghoon
authors: D
authors: Shin
authors: Sandra J
authors: SJ
authors: Lee
authors: Joseph
authors: J
authors: Stuckert
authors: Cindy A
authors: CA
authors: Sander
authors: John M
authors: JM
authors: Kirkwood
mesh_terms: D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood*; D015551:Autoimmunity; D019496:Cancer Vaccines / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005678:G(M2) Ganglioside / Q000276:immunology / Q000627:therapeutic use; D006433:Hemocyanins / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008545:Melanoma / Q000097:blood* / Q000188:drug therapy / Q000276:immunology*; D011379:Prognosis; D012878:Skin Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D019496:Cancer Vaccines; D016898:Interferon-alpha; D005678:G(M2) Ganglioside; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin