Complete eradication of hepatocellular carcinomas by combined vasostatin gene therapy and B7H3-mediated immunotherapy

Abstract

Background/Aims:B7H3 immunogene therapy is able to completely eradicate tumors when combined with an anti-vascular agent. The aim of this study was to determine whether vasostatin, a potent anti-angiogenic agent, could synergize with B7H3-mediated immunotherapy to combat hepatocellular carcinoma (HCC). Methods: Vasostatin and B7H3 expression plasmids were constructed, and the in vitro and in vivo expression and antiangiogenic activity of recombinant vasostatin were measured. The anti-tumor activities of B7H3 and vasostatin alone and in combination were assessed using single and multiple H22 tumor models. Results: Gene transfer of vasostatin inhibited the proliferation of aortic endothelial cells, and angiogenesis in the chorioallantoic membrane assay. Subcutaneous H22 tumors established in BALB/c mice were completely eradicated in response to intratumoral injection of B7H3-expressing plasmids followed 24 h later by vasostatin-expressing plasmids. In contrast, neither vasostatin nor B7H3 monotherapy was effective. Gene transfer of vasostatin inhibited tumor angiogenesis and enhanced infiltration of NK cells, whereas B7H3 therapy activated CD8+ and NK cells and increased their infiltration into tumors, and enhanced the levels of circulating IFN-c. B7H3 and vasostatin combination gene therapy was effective in combating a systemic challenge of parental H22 cells, and caused the complete regression of multiple distant tumor nodules. Conclusions:Combining vasostatin anti-angiogenic therapy with B7H3-mediated immunotherapy warrants investigation as a therapeutic strategy to combat HCC, and other malignancies.