Adjuvant Vaccine Immunotherapy of Resected, Clinically Node-Negative Melanoma: Long-term Outcome and Impact of HLA Class I Antigen Expression on Overall Survival

Abstract

Associations between HLA class I antigen expression and efficacy of a melanoma vaccine (Melacine) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for two years versus observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and pre-specified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging and sex. P=.01 was considered significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by arm. HLA serotyping was performed on 553 (80%) patients (vaccine 294, observation 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n=178) had marginally improved RFS (adjusted P=.02) and significantly improved OS compared with observation arm patients (n=145), with 10-year OS of 75% and 63%, respectively (hazard ratio 0.62, 99% CI 0.37-1.02, P=.01). There was no impact of HLA-A2 and/or HLA-Cw3 expression among observation arm patients. Analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for HLA-A2- and/or HLA-Cw3-expressing melanoma patients. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted.

Utility of cell-based vaccines as cancer therapy: Systematic review and meta-analysis

“…In the adjuvant setting, a study of allogeneic melanoma cell lysate plus the detoxified Freund’s adjuvant compared with observation in resected, clinically node negative melanoma. 38 While the overall endpoint of OS and DFS was not met (statistically insignificant increases in 5-year and 10-year survival), if the analysis was focused on patients who were HLA-A2+ and/or HLA-Cw3+, there were significant differences in both and OS at 5 years 10 years. Other studies of immunotherapy or a similar live vaccinia virus-augmented allogeneic polyvalent melanoma cell lysate did not show significant improvement in survival.…”

Adjuvant NY-ESO-1 vaccine immunotherapy in high-risk resected melanoma: a retrospective cohort analysis

“…Several authors [ 47 – 49 ] have reported data to support the notion that the efficacy of vaccine immunotherapy is perhaps associated with specific HLA genotypes. Of particular interest is work by Carson, et al [ 47 ] who describe the long-term follow-up of an adjuvant melanoma cell lysate-based vaccine in the treatment of resected stage II melanoma. Specifically, the authors found an association between HLA-A2 and improved recurrence-free and overall survival.…”

Long‐term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer

“…In other tumor types, expression levels of PD‐L1 have been linked to OS, DFS, treatment efficacy, and treatment outcomes 7‐9 . CD8 + TILs have been associated with outcomes, 10,11 and HLA class 1 expression has been linked to treatment efficacy, relapse‐free survival, and OS 12,13 …”

“…[7][8][9] CD8 + TILs have been associated with outcomes, 10,11 and HLA class 1 expression has been linked to treatment efficacy, relapse-free survival, and OS. 12,13 Nivolumab is a genetically engineered, fully human IgG4 mAb targeted at human PD-1. 14 A multicenter, open-label, uncontrolled, phase II study evaluated the efficacy and safety of nivolumab in 65 Japanese patients with advanced esophageal cancer refractory or intolerant to standard chemotherapy.…”