Monitoring Tumor Microenvironment Immunotherapeutic Impact in Heterogeneous Cancer: Prostate Cancer, Spatial Transcriptomics, and a Novel Therapeutic Target B7-H3

Background: Localized prostate cancer is notable for tumor heterogeneity, and immune heterogeneity within tumor versus benign areas. B7-H3, a member of the B7 superfamily, is highly expressed (relative to PD-L1 and PD-L2) in prostate cancer, and is associated with rapid biochemical recurrence, early metastases, and differential expression between tumor and benign prostate tissue.  Methods: Enoblituzumab (MacroGenics, Inc.) is an investigational humanized Fc-optimized B7-H3–targeting antibody that induces antibody-dependent cellular cytotoxicity (ADCC). Recently, in a Phase 2 single-arm neoadjuvant trial (NCT02923180) at JHMI, men with operable intermediate- and high-risk localized prostate cancer received enoblituzumab (15 mg/kg IV weekly x 6) prior to surgery. Prostate glands were harvested 2 weeks after the last enoblituzumab dose, and were examined for pathologic and immunologic endpoints. The co-primary outcomes were safety and PSA0 at 1 year post-op.  Results: A total of 32 patients were enrolled. Grade 3/4 drug-related adverse events occurred in 12% of patients; there was no surgical delay due to AEs. PSA0 at 1 year post-op was seen in 66% of men (95% CI: 48-80%). Median time to PSA recurrence was not reached (95% CI: 9.4 months – NE). Gleason grade group changes were significantly associated with treatment compared to 1:1 matched controls. Exploratory tumor microenvironment profiling by NanoString GeoMx spatial proteomics and PanCancer IO 360 mRNA expression analysis revealed evidence of post-treatment upregulation of CD8+ T cells, PD-1/PD-L1, and immune activation (granzyme B, IFN signaling, myeloid inflammation).

Learning objectives:

1. Discuss the Gleeson Score of prostate cancer and the microenvironment but also the high-plex, spatial profiling in pre-treated and post-treatment of B7-H3.

2. Break down the use of spatial proteomic detection, understanding the robust intratumoral induction (adaptive upregulation) of immune checkpoints, T cell activation, and myeloid inflammation in prostate cancer.