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.
Author Info: (1) University of Pittsburgh Medical Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA. (2) Parker Institute for Cancer Immunotherapy, San Francisco, CA. (3)
Author Info: (1) University of Pittsburgh Medical Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA. (2) Parker Institute for Cancer Immunotherapy, San Francisco, CA. (3) Parker Institute for Cancer Immunotherapy, San Francisco, CA. (4) Department of Immunology, University of Pittsburgh, Pittsburgh, PA. (5) University of Pittsburgh Medical Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA. (6) NanoString Technologies, Seattle, WA. (7) Department of Surgery, University of Pittsburgh, Pittsburgh, PA. (8) University of Pittsburgh Medical Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA. (9) University of Pittsburgh Medical Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA. Parker Institute for Cancer Immunotherapy, San Francisco, CA. Department of Immunology, University of Pittsburgh, Pittsburgh, PA. Department of Surgery, University of Pittsburgh, Pittsburgh, PA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
