Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation

4-1BB is an inducible receptor-like protein expressed rapidly by both CD4 a nd CD8 T-cells after,activation. 4-1BB cross-linking. either by binding to 4-1BBL or by antibody ligation, delivers a costimulatory signal to enhance T-cell activation and proliferation. Previous studies have demonstrated tha t the administration of 4-1BB monoclonal antibodies (mAbs) induces antitumo r immune responses. In the current study using several murine tumors, He ex amined the systemic effects of 4-1BB mAb on the growth of s.c. intracranial (i.c.), and pulmonary metastases. In addition, the effects or 4-1BB mAb on the generation of antitumor effector T cells were examined. Treatment of 3 -day i.e. MCA 205 sarcoma and GL261 glioma with the antibody resulted in pr olongation of survival and cure of disease in some mice, whereas only minim al therapeutic effects were observed in established s.c. and pulmonary tumo rs. No antitumor effects against the poorly immunogenic B16/D5 melanoma wer e observed. Interestingly, successful treatment of i.c. tumors induced conc omitant regression of s.c. tumors. Experiments using severe combined immuno deficient mice and mire depleted of either CD4 or CD8 T cells demonstrated T-cell dependence of the antitumor effects. For generation of effector T ce lls in the tumor-draining lymph nodes (LNs). administration of 4-1BB mab ha d adverse effects, despite the apparent hypertrophy of the LNs. During in v itro activation of tumor-draining LN T cells with anti-CD3 and interleukin 2. the 4-1BB mAb augmented proliferation, resulting in an increase in CD8 T cells. However, they were less therapeutic than not treated LN cells. In a doptive immunotherapy, the coadministration of 4-1BB mAb enhanced the thera peutic efficacy. These results thus demonstrate the limits and potential ad vantages of 4-1BB antibody interactions with antitumor T cells in vivo and in vitro and suggest that therapeutic interactions of the antibody may he u sed in a variety of immunotherapeutic approaches.