Extended-Release Immunotherapy-Eluting Embolics

Purpose: Systemic immunotherapy is less effective in patients with liver metastases. Immunoembolization could potentially overcome the immunosuppressive tumor microenvironment, but the optimal immunotherapy agent, embolic, and release kinetics are unknown. Methods: A wide range of immunotherapy agents (cytokines, small molecules, and oligonucleotides) were loaded onto various embolics (stabilized lipiodol emulsions, microspheres-in-lipiodol, LC beads, and PLGA microspheres). Drug loading and release kinetics were evaluated in vitro. A pilot study of transarterial immunoembolization was performed in a pig liver tumor model, using extended release lipiodol/CpG-STAT3ASO formulations. CpG-STAT3ASO is a first-in-class dual-function immunotherapy agent that both stimulates the anti-tumor immune response, and counters immunosuppression in immunologically cold tumors. Safety, pharmacokinetics and efficacy were evaluated in pigs. Results: Immunotherapy-loaded embolics released drug with a half-life ranging from days to weeks in vitro, and up to four days in pig liver tumors (depending on the formulation). A stabilized lipiodol emulsion demonstrated 100% burst release (within five minutes after immunoembolization), compared to <1% burst release with microspheres-in-lipiodol. Immunoembolization using lipiodol/CpG-STAT3ASO resulted in decreased size of pig liver tumors, compared to bland embolization. No adverse events were seen, based on clinical, laboratory, and radiographic evaluation, but peritoneal adhesions were observed in association with immunoembolization using microspheres-in-lipiodol. Conclusions: Extended-release immunotherapy-loaded embolics generate sustained intratumoral delivery of immune stimulants. A pilot study of immunoembolization of pig liver tumors showed decreased tumor size, compared to bland embolization, with no autoimmune adverse events.