Potent antitumor effects mediated by local expression of the mature form of the interferon-γ inducing factor, interleukin-18 (IL-18)

T. Osaki; W. Hashimoto; A. Gambotto; H. Okamura; P. D. Robbins; M. Kurimoto; M. T. Lotze; H. Tahara

doi:10.1038/sj.gt.3300908

Potent antitumor effects mediated by local expression of the mature form of the interferon-γ inducing factor, interleukin-18 (IL-18)

T. Osaki, W. Hashimoto, A. Gambotto, H. Okamura, P. D. Robbins, M. Kurimoto, M. T. Lotze, H. Tahara

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

Abstract

IL-18 is produced during the acute immune response by macrophages and immature dendritic cells. IL-18 receptors are induced on T cells and NK cells by IL-12 and together they enhance a cellular immune response. We constructed retroviral and adenoviral vectors encoding the mature bioactive murine IL-18 in order to examine their immune and antitumor effects in murine tumor models. Secretion of bioactive IL-18 from murine tumor cells was facilitated by transfecting them with recombinant viral vectors carrying the prepro leader sequence of human parathyroid hormone fused to the 5' end of the mature murine IL-18 cDNA. Direct injection of the IL-18 recombinant adenoviral vector (Ad.PTH.IL-18) into an established MCA205 murine fibrosarcoma completely eradicated tumor in all animals with concomitant induction of protective systemic immunity. Co-administration of systemic IL-12 provided synergistic antitumor effects when combined with peritumoral injections of Ad.PTH.IL-18 without apparent side-effects as we observed with systemic administration of IL-18. Depletion of asialo GM-1⁺ cells completely abrogated the antitumor effects of Ad.PTH.IL-18, suggesting a major role for NK cells in mediating the anti-tumor effects of IL-18. Peritumoral injection of Ad.PTH.IL-18 was also associated with reduced numbers of CD8⁺ cells found within the tumor (HBSS versus AdPTH.IL-18, P < 0.0001). This suggests that IL-18 could be utilized as an alternative cancer gene therapy especially when combined with systemic administration of IL-12.

Original language	English (US)
Pages (from-to)	808-815
Number of pages	8
Journal	Gene therapy
Volume	6
Issue number	5
DOIs	https://doi.org/10.1038/sj.gt.3300908
State	Published - 1999
Externally published	Yes

Bibliographical note

Funding Information:
We thank Drs Toru Kitagawa, Yasuhiko Nishioka, Muneo Numasaki, Takuya Takayama, Motohiro Hirao, Shusuke Moriuchi, Hideho Okada, Kazumasa Hiroishi, Hiromune Shimamura and Levent Balkir for their valuable assistance and suggestions. We are also grateful to Ms Loraine R McKenzie and Susan F Schoonover for their excellent technical assistance. This work was supported in part by Career Development Award of American Society of Clinical Oncology ‘94 (HT) and a National Institutes of Health Grant 1PO1 CA 48047–01 (HT, PDR, MTL).

Keywords

Gene therapy
IL-12
Leader sequence
Virus vector

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Potent antitumor effects mediated by local expression of the mature form of the interferon-γ inducing factor, interleukin-18 (IL-18)",

abstract = "IL-18 is produced during the acute immune response by macrophages and immature dendritic cells. IL-18 receptors are induced on T cells and NK cells by IL-12 and together they enhance a cellular immune response. We constructed retroviral and adenoviral vectors encoding the mature bioactive murine IL-18 in order to examine their immune and antitumor effects in murine tumor models. Secretion of bioactive IL-18 from murine tumor cells was facilitated by transfecting them with recombinant viral vectors carrying the prepro leader sequence of human parathyroid hormone fused to the 5' end of the mature murine IL-18 cDNA. Direct injection of the IL-18 recombinant adenoviral vector (Ad.PTH.IL-18) into an established MCA205 murine fibrosarcoma completely eradicated tumor in all animals with concomitant induction of protective systemic immunity. Co-administration of systemic IL-12 provided synergistic antitumor effects when combined with peritumoral injections of Ad.PTH.IL-18 without apparent side-effects as we observed with systemic administration of IL-18. Depletion of asialo GM-1+ cells completely abrogated the antitumor effects of Ad.PTH.IL-18, suggesting a major role for NK cells in mediating the anti-tumor effects of IL-18. Peritumoral injection of Ad.PTH.IL-18 was also associated with reduced numbers of CD8+ cells found within the tumor (HBSS versus AdPTH.IL-18, P < 0.0001). This suggests that IL-18 could be utilized as an alternative cancer gene therapy especially when combined with systemic administration of IL-12.",

keywords = "Gene therapy, IL-12, Leader sequence, Virus vector",

author = "T. Osaki and W. Hashimoto and A. Gambotto and H. Okamura and Robbins, {P. D.} and M. Kurimoto and Lotze, {M. T.} and H. Tahara",

note = "Funding Information: We thank Drs Toru Kitagawa, Yasuhiko Nishioka, Muneo Numasaki, Takuya Takayama, Motohiro Hirao, Shusuke Moriuchi, Hideho Okada, Kazumasa Hiroishi, Hiromune Shimamura and Levent Balkir for their valuable assistance and suggestions. We are also grateful to Ms Loraine R McKenzie and Susan F Schoonover for their excellent technical assistance. This work was supported in part by Career Development Award of American Society of Clinical Oncology {\textquoteleft}94 (HT) and a National Institutes of Health Grant 1PO1 CA 48047–01 (HT, PDR, MTL).",

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doi = "10.1038/sj.gt.3300908",

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T1 - Potent antitumor effects mediated by local expression of the mature form of the interferon-γ inducing factor, interleukin-18 (IL-18)

AU - Osaki, T.

AU - Hashimoto, W.

AU - Gambotto, A.

AU - Okamura, H.

AU - Robbins, P. D.

AU - Kurimoto, M.

AU - Lotze, M. T.

AU - Tahara, H.

N1 - Funding Information: We thank Drs Toru Kitagawa, Yasuhiko Nishioka, Muneo Numasaki, Takuya Takayama, Motohiro Hirao, Shusuke Moriuchi, Hideho Okada, Kazumasa Hiroishi, Hiromune Shimamura and Levent Balkir for their valuable assistance and suggestions. We are also grateful to Ms Loraine R McKenzie and Susan F Schoonover for their excellent technical assistance. This work was supported in part by Career Development Award of American Society of Clinical Oncology ‘94 (HT) and a National Institutes of Health Grant 1PO1 CA 48047–01 (HT, PDR, MTL).

PY - 1999

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N2 - IL-18 is produced during the acute immune response by macrophages and immature dendritic cells. IL-18 receptors are induced on T cells and NK cells by IL-12 and together they enhance a cellular immune response. We constructed retroviral and adenoviral vectors encoding the mature bioactive murine IL-18 in order to examine their immune and antitumor effects in murine tumor models. Secretion of bioactive IL-18 from murine tumor cells was facilitated by transfecting them with recombinant viral vectors carrying the prepro leader sequence of human parathyroid hormone fused to the 5' end of the mature murine IL-18 cDNA. Direct injection of the IL-18 recombinant adenoviral vector (Ad.PTH.IL-18) into an established MCA205 murine fibrosarcoma completely eradicated tumor in all animals with concomitant induction of protective systemic immunity. Co-administration of systemic IL-12 provided synergistic antitumor effects when combined with peritumoral injections of Ad.PTH.IL-18 without apparent side-effects as we observed with systemic administration of IL-18. Depletion of asialo GM-1+ cells completely abrogated the antitumor effects of Ad.PTH.IL-18, suggesting a major role for NK cells in mediating the anti-tumor effects of IL-18. Peritumoral injection of Ad.PTH.IL-18 was also associated with reduced numbers of CD8+ cells found within the tumor (HBSS versus AdPTH.IL-18, P < 0.0001). This suggests that IL-18 could be utilized as an alternative cancer gene therapy especially when combined with systemic administration of IL-12.

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Potent antitumor effects mediated by local expression of the mature form of the interferon-γ inducing factor, interleukin-18 (IL-18)

Abstract

Bibliographical note

Keywords

UN SDGs

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