Genetic immunotherapy of lung cancer using conditionally replicating adenovirus and adenovirus-interferon-beta.
Genetic immunotherapy is considered an ideal treatment modality for cancer because of its systemic nature. This study was designed to develop a potent novel genetic immunotherapy by combining conditionally replicating adenovirus (CRAd) and replication-defective adenovirus expressing interferon-beta (ad-IFN-beta). We investigated the efficacy of this therapy in an immunocompetent mouse tumor model. Transduction with CRAd (Delta24RGD) induced cytolysis in a mouse lung cancer cell line (Lewis lung carcinoma (LLC)). Combined transduction of ad-IFN-beta and Delta24RGD in the LLC cells induced a greater and more prolonged production of IFN-beta. Media transfer from the LLC-Delta24RGD-ad-IFN-beta to untransduced LLC cells induced the production of IFN-beta; these results confirmed the replication and release of ad-IFN-beta. LLC cells transduced with ad-IFN-beta and Delta24RGD had decreased tumorigenicity in syngeneic mice. Tumor vaccination with irradiated LLC-ad-IFN-beta-Delta24RGD showed a significant increase in the survival of tumor-bearing syngeneic mice compared with mice with a single transduced LLC vaccination; this was mediated by an enhanced cytotoxic T-lymphocyte response against the LLC cells. The results of this study showed that cotransduced Delta24RGD to ad-IFN-beta aided the replication of ad-IFN-beta in the LLC cells. A high local concentration of IFN-beta and local release of tumor antigen by CRAd induced strong antitumor immunity. This combination strategy might provide a powerful means by which ad-cytokines and CRAd can be combined and other adenoviruses expressing different cytokines might also be used.
Park
M-Y
MY
Department of Internal Medicine, Seoul National University Bundang Hospital, Gyeonggi-Do, Republic of Korea.
Kim
D R
DR
Jung
H W
HW
Yoon
H-I
HI
Lee
J H
JH
Lee
C-T
CT
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL
D016899:Interferon-beta