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

Response of Locally Advanced Pancreatic Cancer to Intratumoral Injection of Large Surface Area Microparticle Paclitaxel

“…Evaluation of IT LSAM-PTX when used with immunotherapy is of particular interest given the immune responses 34 including immune cell infiltration and increased checkpoint expression on immune effector cells within the tumor site after IT LSAM-PTX. Similar observations were noted after local LSAM-DTX treatment of bladder cancer 17,20 . Injection of LSAM-PTX or LSAM-DTX particles into an orthotopic breast cancer model demonstrates synergistic tumoricidal responses in combination with a systemic checkpoint inhibitor 35 .…”

“…Similar observations were noted after local LSAM-DTX treatment of bladder cancer. 17,20 Injection of LSAM-PTX or LSAM-DTX particles into an orthotopic breast cancer model demonstrates synergistic tumoricidal responses in combination with a systemic checkpoint inhibitor. 35 Taken together, these observations encourage combinatorial trials with IT LSAM-PTX and IV checkpoint inhibitors in patients with LAPC to reduce local and metastatic disease and prolong survival.…”

“…The relatively large particle size facilitates entrapment, and the large surface area allows for continuous drug release in the tumor over an extended time. Clinical trials evaluating LSAM-PTX and LSAM-Docetaxel (LSAM-DTX) 11,17 have been conducted in prostate cancer, peritoneal malignancies, 18 ovarian cancer, 19 bladder cancer, 20 and pancreatic cystic neoplasms 21 . Local administration results in negligible systemic exposure 11,17,20 .…”

“…Clinical trials evaluating LSAM-PTX and LSAM-Docetaxel (LSAM-DTX) 11,17 have been conducted in prostate cancer, peritoneal malignancies, 18 ovarian cancer, 19 bladder cancer, 20 and pancreatic cystic neoplasms 21 . Local administration results in negligible systemic exposure 11,17,20 . Large surface area microparticle paclitaxel is an investigational product not yet approved for use by the US Food and Drug Administration.…”

Early phase trial of intracystic injection of large surface area microparticle paclitaxel for treatment of mucinous pancreatic cysts

“…A particle-engineered form of paclitaxel has been developed, resulting in large surface area microparticle paclitaxel (LSAM-PTX, NanoPac, CritiTech, Inc., Lawrence, Kansas, United States) with a mean particle size of 3 to 4 microns, surface area > 24 m 2 /g and containing approximately 2 billion paclitaxel molecules each, to address the limitation of short-term, intermittent systemic exposure to the cytotoxic agent when injected into lesions or tumors 26 27 . LSAM-PTX and LSAM-DTX (LSAM docetaxel) are undergoing clinical trials as intratumoral therapy for a number of solid carcinomas 27 28 .…”