Targeting Spatiotemporal Expression of CD137 on Tumor-infiltrating Cytotoxic T Lymphocytes as a Novel Strategy for Agonistic Antibody Therapy

CD137 (4-1BB) is an important costimulatory ligand and a potent stimulator of T-cell responses. It has been used therapeutically to stimulate immunity against several solid malignancies as well as to modulate susceptibility to autoimmune disease and infection. However, clinical trials of anti-CD137 agonistic antibody have been suspended because of deleterious side effects. To overcome this problem, we fine-tuned the combination of adoptive transfer of tumor-specific cytotoxic T lymphocytes (CTL) and anti-CD137 monoclonal antibody (mAb) treatment. B16 melanoma cells (1 x 10(6)) were implanted subcutaneously in C57BL/6 mice. On day 9, CTLs (1 x 10(7)) were intravenously injected into tumor-bearing mice. Transferred CTL distributed throughout the body and infiltrated into the tumor. CD137 expression was upregulated on tumor-infiltrating CTL, but not in other tissues or other cell types. Therefore, mice received anti-CD137 mAb (100 mu g) 3 days after CTL transfer. interferon-g was produced in the tumor only by transferred CTL, not recipient-derived cells. The functional CTLs in the tumor were increased and interferon-g production per cell was augmented by anti-CD137 treatment. It was not detected in CTL found in other tissues. Consistent with this, no organ damage was observed on anti-CD137 treatment. On the basis of the spatiotemporal expression of CD137 on tumor-infiltrating CTLs, anti-CD137 mAb selectively activated these tumor-infiltrating cells, augmented their antitumor activity and greatly decreased tumor growth. Tumor-specific CTL can guide agonistic anti-CD137 mAb to the tumor and in turn, become functionally augmented. Thus, CD137 mAb therapy may become feasible again in combination with tumor-specific CTL therapy.