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Cotransduction of CCL27 gene can improve the efficacy and safety of IL-12 gene therapy for cancer

Gene Therapy volume 14, pages 491–502 (2007)Cite this article

Abstract

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-γ. 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.

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Abbreviations

AdRGD:

RGD fiber-mutant adenoviral vector

CCL:

CC-chemokine ligand

CTL:

cytotoxic T lymphocyte

DC:

dendritic cell

FBS:

fetal bovine serum

HE:

hematoxylin and eosin

IFN:

interferon

IL:

interleukin

mAb:

monoclonal antibody

NK:

natural killer

PBS:

phosphate-buffered saline

PFU:

plaque-forming unit

RT-PCR:

reverse transcription-polymerase chain reaction

STAT:

signal transducer and activator of transcription

TAA:

tumor-associated antigen

Th:

helper T

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Acknowledgements

We are grateful to Professor Osamu Yoshie and Dr Takashi Nakayama (Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Japan) for providing a plasmid-containing murine CCL27 cDNA, to Professor Hiroshi Yamamoto (Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan) for providing murine IL-12 cDNA-containing plasmid, GK1.5 ascites and 53–6.72 ascites, to Dr Hiromi Fujiwara for providing OV-HM and Meth-A cells, to Professor Nicholas P Restifo (National Cancer Institute, Bethesda, MD, USA) for providing CT26 cells and to Mr Alexandre Learth Soares and Mr Feng Qiu (Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan) for their technical assistance. The present study was supported in part by grants from the Ministry of Health, Labour and Welfare of Japan, by a Grant-in-Aid for Scientific Research on Priority Areas (17016043) and Young Scientists (A) (18689007) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by grant from the Takeda Science Foundation.

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Author notes

  1. J-Q Gao

    Present address: Institute of Pharmaceutics, Zhejiang University, 353 Yan-an Road, Hangzhou, 310031, P.R. China

  2. J-Q Gao and N Kanagawa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan

    J-Q Gao, N Kanagawa, Y Motomura, T Yanagawa, T Sugita, N Okada & S Nakagawa

  2. Department of Biomedical Science, Dako Japan Co., Ltd, Nishinotouin-higashiiru, Shijo-dori, Shimogyo-ku, Kyoto, Japan

    Y Hatanaka & Y Tani

  3. National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

    H Mizuguchi & Y Tsutsumi

  4. Kobe-gakuin University, Igawadani, Nishi-ku, Kobe, Japan

    T Mayumi

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Correspondence to N Okada or S Nakagawa.

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Gao, JQ., Kanagawa, N., Motomura, Y. et al. Cotransduction of CCL27 gene can improve the efficacy and safety of IL-12 gene therapy for cancer. Gene Ther 14, 491–502 (2007). https://doi.org/10.1038/sj.gt.3302892

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