Preclinical Development and Validation of Translational Temperature Sensitive Iodized Oil Emulsion Mediated Transcatheter Arterial Chemo-Immuno-Embolization for the Treatment of Hepatocellular Carcinoma.

Substantial research has been conducted on effective approaches for harnessing the antitumor potential of combination immunotherapies directed at the tumor. The synergistic enhancement of cancer therapeutic efficacy can be achieved through the combination of interventional oncology therapies and local immunotherapy. In this study, w e present a practical strategy for augmenting immune activation in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Pluronic F127 (PF127) w as incorporated with Lipiodol (LPD) to achieve safe and effective delivery of therapeutic agents during transcatheter intra-arterial local delivery. W e demonstrated enhanced emulsion stability, intra-arterial infusion, embolic effect, safety, pharmacokinetics, and tumor response of Doxorubicin loaded PF127-LPD (Dox-PF127-LPD) for TACE in both in vitro and in vivo preclinical VX2 liver cancer rabbit model and N1S1 HCC rat model. Then, transcatheter arterial chemo-immuno-embolization (TACIE) combining TACE and local delivery of immune adjuvant (TLR9 agonist CpG oligodeoxynucleotide) w as successfully performed using CpG loaded Dox-PF127-LPD. Concurrent and safe local delivery of CpG and TACE during TACIE demonstrated leveraged TACE-induced immunogenic tumor microenvironment and augmented systemic anti-tumor immunity in syngeneic N1S1 HCC rat model. Finally, the broad utility and enhanced therapeutic efficacy of TACIE w ere validated in diethylnitrosamine (DEN)-induced rat HCC model. TACIE using clinically established protocol and materials should be a convenient and powerful therapeutic approach that can be translated to patients with HCC. Robust anti-cancer immunity and effective tumor response of TACIE, couple with its safety profile, suggests that it may represent a new form of local combination immunotherapy for the treatment of HCC. This article is protected by copyright. All rights reserved.