Anti‐OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer

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Abstract
The therapeutic effect of agonistic anti‐OX40 (CD134) monoclonal antibody (mAb) in combination with radiotherapy was evaluated in a murine lung cancer model. After intradermal transplantation of ovalbumin (OVA)‐transfected Lewis lung carcinoma, C57BL/6 mice were irradiated locally with a single dose of 20 Gy in combination with an intratumoral injection of anti‐OX40 mAb at 50 µg on day 4 after transplantation, which is when the major axis of the inoculated tumor reached a diameter of 7–9 mm. On days 8, 11, and 14, the tumor‐bearing mice were further treated with the same dose of anti‐OX40 mAb. Anti‐OX40 mAb in combination with radiotherapy prolonged survival and provided greater efficacy than either single treatment against well‐established tumors. An in vivo depletion study suggested that therapeutic immunity was mainly CD8+ T‐cell dependent. OX40+CD8+ T cells were augmented in draining lymph nodes obtained from irradiated mice compared with those from non‐irradiated mice. OVA‐major histocompatibility complex tetramer+ CD8+ T cells had been strongly recruited to the draining lymph nodes obtained from mice treated with anti‐OX40 mAb in combination with radiotherapy, and strong antigen‐specific cytotoxicity was confirmed by a 51Cr‐release assay. Moreover, a tumor‐rechallenge model indicated that this combination therapy induced durable tumor immunity. Thus, anti‐OX40 mAb in combination with radiotherapy may potentially help the management of patients with lung cancer. (Cancer Sci 2008; 99: 361–367)