Combination therapy of radiation and interleukin 12 induced regression of large orthotopic liver cancers by modulation of tumor microenvironment (VAC12P.1111)

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide with few therapeutic options. Radiation is one of the mainstay cancer therapies. We hypothesize that combination of radiation and local interleukin 12 (IL-12) immunotherapy may change the suppressive tumor microenvironment to a proinflammatory condition favorable in induction of antitumor immune responses. IL-12 has potent antitumor activities through activation of CD8+ T cells and natural killer cells, reprogramming several types of myeloid-derived suppressor cells to a phenotype that favors immune activation, and inhibiting new blood vessel formation within tumors. Our data showed that combination of radiation and intratumoral injection of an adenoviral vector encoding IL-12 (Ad/IL-12) led to tumor regression in the majority of animals bearing large orthotopic hepatocellular carcinoma and significantly prolonged their survival. Single treatment of radiation or Ad/IL-12 delayed tumor growth but did not result in tumor regression. Mechanistic studies revealed that combination therapy greatly increased the cell numbers and activities of tumor-infiltrating CD8+ T cells, while the cell numbers and suppressive functions of MDSC and tumor-associated macrophages (TAM) were significantly decreased. Our results strongly suggest that a combinatorial treatment of radiation and IL-12 may represent an alternative therapy for advanced HCC.