PSMA-Targeted Activated Myeloid Cells as a Novel Prostate Cancer Immunotherapy
Abstract
Immature myeloid cells lacking NF-kB p50 (p50-IMC) slows growth of prostate cancer (PrCa), given after a dose of 5FU. We hypothesize that co-administering PSMA antibody (Ab) or expressing a PSMA-targeting chimeric antigen receptor (CAR) onp50-IMC will direct p50-IMC to PrCa and enable phagocytosis, increasing efficacy. EGFR is also expressed on a subset of aggressive PrCa tumors. We find that wild-type (WT) or p50(-/-) macrophages minimally phagocytose Myc-CaP PrCa cells expressing human PSMA or EGFR, but that PSMA or EGFR Ab and PSMA CAR markedly increase phagocytosis in both IFNg(M1) or IL-4 (M2) culture conditions. We also find that PSMA Ab increased p50-IMC localization to Myc-CaP/hPSMA tumors in NSG mice, with preceding 5FU increasing localization. As immune-competent FVB/N mice reject Myc-CaP cells expressinghPSMA or hEGFR we developed transgenic mice expressing hPMSA in the prostate; however; while RNA was abundant,protein was absent. We also developed transgenic mice expressing truncated hEGFR; we detect protein expression and have germline transmission, which should enable efficacy studies using p50-IMC and EGFR Ab or CAR. We constructed a mutant PSMA lacking its cytoplasmic domain and with mutation in its enzymatic active site, and confirmed its PSMA Ab binding, withplans to obtain transgenic mice expressing this variant for efficacy studies using p50-IMC with PSMA Ab or CAR.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1217539
Entities
People
- Alan Friedman
Organizations
- Johns Hopkins University