Reversing gp100/IFA-induced impairment of anti-CTLA-4 checkpoint blockade therapy

Background and hypothesis Cancer immunotherapies have been advanced by the recent FDA approval of anti-CTLA-4 antibody (Ipilimumab, Yervoy) and soon-to-be approved anti-PD-1 antibody, immunological checkpoint-blocking agents with significant anti-tumor activity against melanoma and other cancers. A promising avenue to further increase their efficacy is combination with T cell-inducing vaccination. Surprisingly, addition of gp100 peptide vaccination did not increase but actually decreased clinical efficacy to antiCTLA-4 in melanoma patients [1]. As a result, it is currently unclear how to combine anti-CTLA-4 with vaccination. We recently reported [2] that vaccination with gp100 peptide in IFA creates a persisting antigen depot that primes antigen-specific CD8+ T cells, followed by their undesirable sequestration at the vaccination site, and eventually their exhaustion and apoptosis, resulting in negligible anti-tumor activity. Here, we investigate whether this phenomenon can also explain the lack of synergy between IFA-based vaccination and antiCTLA-4 therapy.