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Mol Ther. 2002 Oct;6(4):528-36.

OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases.

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Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.


Previously, we showed that the eradication of murine hepatic metastatic colon carcinomas was achieved by using a combination therapy with adenovirus-mediated gene delivery of interleukin 12 (IL-12) and anti-4-1BB agonistic antibody. However, the therapeutic efficacy was compromised severely when mice with tumors larger than 8 x 8 mm(2) were treated. In this report, we studied the effect of OX40 costimulation through agonistic anti-OX40 in combination with the IL-12 + anti-4-1BB immunotherapy on primary and memory anti-tumor cytotoxic T lymphocyte responses in a large-tumor setting (8 x 8 to 12 x 12 mm(2)). Tumor-infiltrating leukocytes (TILs) isolated from mice treated with the combination therapy of IL-12, anti-4-1BB, and anti-OX40 showed a significantly higher ex vivo direct cytotoxic T lymphocyte (CTL) activity against parental tumors, as compared with those from mice treated with IL-12 and anti-4-1BB. In vivo depletion of CD4(+)T cells during combination therapy significantly decreased the number of tumor-infiltrating CD8(+)T cells and their cytotoxic activity in mice treated with IL-12 + anti-4-1BB + anti-OX40 combination therapy but not in the group treated with IL-12 + anti-4-1BB, which indicated that in vivo OX40 engagement on CD4(+) T cells led to the higher CTL responses observed in animals treated with IL-12 + anti-4-BB + anti-OX40 combination therapy. Furthermore, the combination therapy of IL-12, anti-4-1BB, and anti-OX40 resulted in a significantly higher survival rate in treated mice, as compared with treatment with IL-12 and anti-4-1BB. More importantly, long-term surviving mice from the combination therapy with IL-12, anti-4-1BB, and anti-OX40 exhibited higher memory CTL responses against parental tumor cells. The results demonstrated that OX40 ligation of CD4(+) T cells facilitated the development of primary and memory CTL responses against tumorcells and that coordinated immune activation by IL-12, anti-4-1BB, and anti-OX40 resulted in a significantly higher survival rate in mice with large tumor burdens. Thus, the combination therapy with the adenovirus encoding IL-12 (Adv.mIL-12) + anti-4-1BB + anti-OX40 antibodies may provide a better treatment modality for patients with advanced cancers, often associated with a state of immune suppression or tolerance.

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