Santos et al. characterized the CD8+ T cells of patients enrolled in a phase I clinical trial who were treated with dendritic cell (DC) vaccines engineered to express three melanoma antigens (MA; tyrosinase, MART-1, and MAGE-A6). Antigen expression levels in DCs did not correlate with T cell response or clinical outcome. Combined, but not individual, CD8+ T cell response to the vaccine correlated with improved PFS and weakly with OS. Patients with low PD-1 expression on MA-specific CD8+ T cells demonstrated better clinical response, but in vitro PD-1 blockade on PD-1high T cells had no significant effect on antigen-specific T cell activity.
Contributed by Shishir Pant
ABSTRACT: Immune and molecular profiling of CD8 T cells of patients receiving DC vaccines expressing three full-length melanoma antigens (MAs) was performed. Antigen expression levels in DCs had no significant impact on T cell or clinical responses. Patients who received checkpoint blockade before DC vaccination had higher baseline MA-specific CD8 T cell responses but no evidence for improved functional responses to the vaccine. Patients who showed the best clinical responses had low PD-1 expression on MA-specific T cells before and after DC vaccination; however, blockade of PD-1 during antigen presentation by DC had minimal functional impact on PD-1high MA-specific T cells. Gene and protein expression analyses in lymphocytes and tumor samples identified critical immunoregulatory pathways, including CTLA-4 and PD-1. High immune checkpoint gene expression networks correlated with inferior clinical outcomes. Soluble serum PD-L2 showed suggestive positive association with improved outcome. These findings show that checkpoint molecular pathways are critical for vaccine outcomes and suggest specific sequencing of vaccine combinations.