Laboratory Investigation
Therapeutic Effect of Irreversible Electroporation in Combination with Poly-ICLC Adjuvant in Preclinical Models of Hepatocellular Carcinoma

https://doi.org/10.1016/j.jvir.2019.02.023Get rights and content

Abstract

Purpose

To evaluate the therapeutic efficacy of irreversible electroporation (IRE) combined with the intratumoral injection of the immunogenic adjuvant poly-ICLC (polyinosinic-polycytidylic acid and poly-L-lysine, a dsRNA analog mimicking viral RNA) inmediately before IRE.

Materials and Methods

Mice and rabbits bearing hepatocellular carcinoma tumors (Hepa.129 and VX2 tumor models, respectively) were treated with IRE (2 pulses of 2500V), with poly-ICLC, or with IRE + poly-ICLC combination therapy. Tumor growth in mice was monitored using a digital caliper and by computed tomography in rabbits.

Results

Intratumoral administration of poly-ICLC immediately before IRE elicited shrinkage of Hepa.129 cell-derived tumors in 70% of mice, compared to 30% and 26% by poly-ICLC or IRE alone, respectively (P = .0004). This combined therapy induced the shrinkage of VX-2-based hepatocellular carcinoma tumors in 40% of rabbits, whereas no response was achieved by either individual treatment (P = .045). The combined therapy activated a systemic antitumor response able to inhibit the growth of other untreated tumors.

Conclusions

IRE treatment, immediately preceded by the intratumoral administration of an immunogenic adjuvant such as poly-ICLC, might enhance the antitumor effect of the IRE procedure. This combination might facilitate the induction of a long-term systemic response to prevent tumor relapses and the appearance of metastases.

Section snippets

Materials and Methods

This study was approved by the Institutional Animal Care and Use Committee (Ref. 111-15). and conformed to U.S. National Institutes of Health guidelines for the humane handling of laboratory animals.

Therapeutic Effect of IRE in Combination with a Poly-ICLC Adjuvant in a Murine Model for HCC

Mice bearing Hepa-129 tumors (>5 mm in diameter) were randomly divided into different experimental groups (n = 10–17; see Materials and Methods section) and treated with: (i) IRE (n = 15), (ii) intratumoral injection of poly-ICLC (n = 10), (iii) intratumoral injection of poly-ICLC immediately followed by IRE (n = 17), or (iv) left untreated (tumor growth control group) (n = 12). It was found that, while treatment of mice with IRE alone or poly-ICLC alone induced tumor shrinkage in 26.6% and 30%

Discussion

Clinical trials have shown that IRE is safe but still inefficient for long-term control of disease 5, 20, 21. This long-term control could be achieved if an immune response against the tumor was elicited. IRE produces cellular destruction causing the release of a substantial amount of tumor-specific antigens that can be engulfed by dendritic cells (DCs) for their presentation to tumor-specific T lymphocytes. The efficient priming of these T lymphocytes is only achieved when DCs are at a mature

Acknowledgments

The study was supported by grants from PIUNA Universidad de Navarra, FIMA, Ministerio de Economia y Competitividad (SAF2016-78568-R), “Murchante se mueve contra el cancer” and Fundación Bancaria La Caixa-Hepacare Project.

We thank Elena Ciordia, Gloria Abizanda, Igor Alkain, and Alberto Espinal for excellent animal care; Andoni Fourco for helping in the design of electrodes for the IRE system; and Mikel Ariz and Laura Guembe for the histologic analyses. We also thank Dr. Andres Salazar for

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