Augmentation versus inhibition: Effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor

Therapeutic efficacy of adoptive immunotherapy of malignancies is proportio nal to the number of effector T cells transferred. Traditionally, exogenous IL-2 treatment has been used to promote the survival and function of trans ferred cells. Recently, we described the therapeutic effects of in vivo lig ation of the costimulatory receptor, OX-40R, on activated T cells during ea rly tumor growth. In this study, we examined the effects of IL-2 and OX-40R mAb on adoptive immunotherapy of advanced tumors. For treatment of 10-day 3-methylcholanthrene 205 pulmonary metastases, systemic transfer of 50 X 10 (6) activated tumor-draining lymph node T cells resulted in > 99 % reductio n of metastatic nodules. With either IL-2 or OX-40R mAb conjunctional treat ment, only 20 X 10(6) Cells were required. Advanced 10-day 3-methylcholanth rene 205 intracranial tumors could be cured by the transfer of 15 X 10(6) L -selectin(low) T cells derived from draining lymph nodes. In this situation , IL-2 administration inhibited therapeutic effects of the transferred cell s. By contrast, 5 X 10(6) T cells were sufficient to cure all mice if OX-40 R mAb was administrated. Studies on trafficking of systemically transferred T cells revealed that IL-2, but not OX-40R mAb, impeded tumor infiltration by T cells. Tumor regression required participation of both CD4 and CD8 T cells. Because only CD4 T cells expressed OX-40R at cell transfer, direct C D4 T cell activation is possible. Alternatively, OX-40R might be up-regulat ed on transferred T cells at the tumor site, rendering them reactive to the mAb. Our study suggests OX-40R mAb to be a reagent of choice to augment T cell adoptive immunotherapy in clinical trials.