Complete eradication of hepatocellular carcinomas by combined vasostatin gene therapy and B7H3-mediated immunotherapy.
OBJECTIVE
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 anti-angiogenic 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 24h 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-gamma. 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.
Ma
Lixin
L
The Hepatosplenic Surgery Center of Heilongjiang Province/Department of General Surgery, The First Clinical College of Harbin Medical University, Harbin 150001, China.
Luo
Liqiong
L
Qiao
Haiquan
H
Dong
Xuesong
X
Pan
Shangha
S
Jiang
Hongchi
H
Krissansen
Geoffrey W
GW
Sun
Xueying
X
D000818:Animals; D060887:B7 Antigens; D018122:B7-1 Antigen / Q000235:genetics; D001483:Base Sequence; D037282:Calreticulin / Q000235:genetics*; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D007167:Immunotherapy / Q000379:methods*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010446:Peptide Fragments / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D014162:Transfection
D060887:B7 Antigens; D018122:B7-1 Antigen; D037282:Calreticulin; C486038:Cd276 protein, mouse; D010446:Peptide Fragments; D011994:Recombinant Proteins; C121986:vasostatin