Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model.
OBJECTIVE
We investigated whether an armed viral platform, where lytic property of a viral infection is coupled to viral-mediated delivery of therapeutic genes, could increase the therapeutic potential of a viral-based therapy.


METHODS
We generated interleukin (IL)-12-expressing oncolytic adenovirus (YKL-IL-12) and IL-12- and B7-1-expressing (YKL-IL12/B7) oncolytic adenovirus. Therapeutic efficacy of these newly engineered adenoviruses was then evaluated in vivo using an immunocompetent mouse bearing murine melanoma B16-F10 tumors. Overall survival was assessed with the Kaplan-Meier method. The induction of immune cell cytotoxicity was assessed by CTL assay, IFN-gamma enzyme-linked immunospot assay, and immunohistochemical studies.


RESULTS
YKL-IL12/B7 oncolytic adenovirus, expressing both IL-12 and B7-1, showed a higher incidence of complete tumor regression compared with the analogous oncolytic adenovirus, YKL-1, or IL-12-expressing, YKL-IL12. Significant survival advantage was also seen in response to YKL-IL12/B7. Moreover, IL-12 and IFN-gamma levels produced in tumors treated with YKL-IL12/B7 was significantly greater than those treated with YKL-IL12. The enhanced survival advantage was mediated by the induction of immune cell cytotoxicity. In agreement with these results, massive infiltration of CD4(+) and CD8(+) T cells into tissues surrounding the necrotic area of the tumor was observed following in situ delivery of YKL-IL12/B7.


CONCLUSIONS
Combination of oncolysis and the enhancement of antitumor immune response by oncolytic adenovirus expressing both IL-12 and B7-1 elicits potent antitumor effect and survival advantage.
Lee
Young-Sook
YS
Brain Korea 21 Project for Medical Science, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, Korea.
Kim
Joo-Hang
JH
Choi
Kyung-Ju
KJ
Choi
Il-Kyu
IK
Kim
Hoguen
H
Cho
Sungae
S
Cho
Byoung Chul
BC
Yun
Chae-Ok
CO
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004359:Drug Therapy, Combination; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D018122:B7-1 Antigen; D018664:Interleukin-12; D007371:Interferon-gamma