Spatial proteomic analysis reveals vaccine and PD-1 blockade elicits changes to the prostate tumor immune microenvironment with infiltration of dendritic cells and activated CD8 T cells 2502

Description We have previously shown in murine tumor models that PD-L1 blockade improves anti-tumor vaccine efficacy. In 66 patients with metastatic, castration-resistant prostate cancer, we reported that concurrent, but not sequential, treatment with DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) and PD-1 blockade resulted in PSA declines in 35% (>50% declines in 10%) patients, reductions in tumor volumes, and 47.2% six-month progression free survival (PFS) rate [NCT02499835]. Immune-related adverse events (irAEs) correlated with prolonged stable disease or PSA declines. Tumor biopsies obtained pre- and post-treatment from the same metastatic sites of 12 patients were analyzed using Nanostring nCounter and GeoMx platforms. Responders (PSA ↓ >50% or PFS > 6 months) showed increased antigen presentation and T cell activation related marker expression, dendritic cell infiltration and reduced checkpoint marker expression. Non-responders exhibited immune-suppressive pathways, including higher expression of immune checkpoints and myeloid-derived suppressor cell (MDSC)-associated markers. Increased PARP expression in non-responders and in patients w/o irAEs suggested a potential resistance mechanism. These findings emphasize the role of tumor-infiltrating antigen presenting cells and T cell activation in therapeutic response to vaccine + PD-1 blockade and suggest that further combination with PARP inhibition or treatments targeting MDSC might increase treatment efficacy. Funding Sources Grant support was provided by NIH (P30 CA014520 and R01 CA129154), a 2014 Movember-PCF Challenge Award from the Prostate Cancer Foundation, and with funding support by Madison Vaccines, Inc.