Cotransduction of CCL27 gene can improve the efficacy and safety of IL-12 gene therapy for cancer.
Interleukin-12 (IL-12) is a potent antitumoral cytokine, but high doses are toxic. Herein, we demonstrate that combinational transduction of IL-12 and CC-chemokine ligand-27 (CCL27) genes into pre-existing murine OV-HM ovarian carcinoma and Meth-A fibrosarcoma, by using RGD fiber-mutant adenoviral vectors, could induce tumor regression and relieve systemic side effects more effectively than either treatment alone. The antitumor activity of the IL-12 and CCL27 combination treatment was T-cell-dependent, and development of long-term specific immunity was confirmed in rechallenge experiments. Immunohistochemical analysis of tumors transduced with CCL27 gene alone or cotransduced with IL-12 and CCL27 genes showed significant increases in numbers of infiltrating CD3(+) T cells, which included both CD4(+) and CD8(+) cells. Additionally, cotransduction with IL-12 and CCL27 genes could more efficiently activate tumor-infiltrating immune cells than transduction with CCL27 alone, as determined by the frequency of perforin-positive cells and expression levels of IFN-gamma. Furthermore, mice treated with the IL-12 and CCL27 combination compared with those treated with IL-12 alone showed milder pathological changes, for example, lymphocyte infiltration and extramedullary hematopoiesis, in lung, liver and spleen. Our data provide evidence that combinational in vivo transduction with IL-12 and CCL27 genes is a promising approach for the development of cancer immunogene therapy that can simultaneously recruit and activate tumor-infiltrating immune cells.
Gao
J-Q
JQ
Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Kanagawa
N
N
Motomura
Y
Y
Yanagawa
T
T
Sugita
T
T
Hatanaka
Y
Y
Tani
Y
Y
Mizuguchi
H
H
Tsutsumi
Y
Y
Mayumi
T
T
Okada
N
N
Nakagawa
S
S
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D054425:Chemokine CCL27; D019742:Chemokines, CC / Q000235:genetics* / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006411:Hematopoiesis, Extramedullary; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy*; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D013154:Spleen / Q000473:pathology; D014161:Transduction, Genetic / Q000379:methods*
C119538:Ccl27a protein, mouse; D054425:Chemokine CCL27; D019742:Chemokines, CC; D018664:Interleukin-12; D007371:Interferon-gamma