Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer.
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 microg 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 (51)Cr-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.
Yokouchi
Hiroshi
H
First Department of Medicine, Hokkaido University, School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-0815, Japan. yokouchi@med.hokudai.ac.jp
Yamazaki
Koichi
K
Chamoto
Kenji
K
Kikuchi
Eiki
E
Shinagawa
Naofumi
N
Oizumi
Satoshi
S
Hommura
Fumihiro
F
Nishimura
Takashi
T
Nishimura
Masaharu
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000276:immunology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018714:Radiotherapy, Adjuvant; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053262:Receptors, OX40