Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model

Immunotherapyholds promise for multiple myeloma (MM) patients but little is known about how MM-induced immunosuppression influences response to therapy. Here, we investigated the impact of disease progression on immunotherapyefficacy in the Vk*MYC mouse model. Treatment with agonistic anti- CD137(4-1BB) mAbs efficiently protected mice when administered early but failed to contain MM growth when delayed more than three weeks after Vk*MYC tumor cell challenge. The quality of CD8+ T cell response to CD137stimulation was not altered by the presence of MM, but CD8+ T cell numbers were profoundly reduced at the time of treatment. Our data suggest that an insufficient ratio of CD8+ T cells over MM cells ( CD8/MM) accounts for the loss of anti- CD137mAb efficacy. We established serum M-protein levels prior to therapy as a predictive factor of response. Moreover, we developed an in silico model to capture the dynamic interactions between CD8+ T cells and MM cells. Finally, we explored two methods to improve the CD8/MM ratio: anti- CD137mAb immunotherapycombined with Treg-depletion or administered after chemotherapy treatment with cyclophosphamide or melphalanefficiently reduced MM burden and prolonged survival. Altogether, our data indicate that consolidation treatment with anti- CD137mAbs might prevent MM relapse.