Local administration of large surface area microparticle docetaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects: preclinical and clinical studies

Abstract

This report describes local administration of large surface area microparticle docetaxel (LSAM-DTX: ~ 3.5- to 7.5-µm-sized particles with high relative surface area) in preclinical oncology models and in a clinical trial in urothelial carcinoma. Reductions in tumor volumes were found following intratumoral (IT) injection of LSAM-DTX into human urologic carcinoma cell lines and syngeneic murine renal and breast cancer cell lines. Compared to IT injections of docetaxel solution typically administered intravenously, IT LSAM-DTX results in 40-fold more docetaxel retained within the tumor. The long residence time of LSAM-DTX within the tumor acts as a drug depot, allowing for continuous release of docetaxel, exposing tumor cells to high, therapeutic levels of chemotherapeutic for several weeks. Local LSAM-DTX results in tumoricidal effects at the site of deposition as well as in distant tumors, and IT LSAM-DTX in combination with immune checkpoint inhibitor therapy reduces or eliminates metastatic spread. Tumoricidal effects of local LSAM-DTX are accompanied by immunomodulation including increases in innate and adaptive immune cells in the tumor microenvironment and peripheral blood. Encouraging clinical results indicate that local administration of LSAM-DTX may provide therapeutic benefits for non-muscle invasive bladder cancer and muscle invasive bladder cancer patients; treatments were well-tolerated with few local and systemic adverse events and negligible systemic docetaxel exposure. Results of preclinical and clinical investigations summarized here indicate that local administration of LSAM-DTX may augment tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Graphical abstract: [Figure not available: see fulltext.].