ABSTRACT
Immunotherapy holds 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 immunotherapy efficacy 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 CD137 stimulation 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-CD137 mAb 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-CD137 mAb immunotherapy combined with Treg-depletion or administered after chemotherapy treatment with cyclophosphamide or melphalan efficiently reduced MM burden and prolonged survival. Altogether, our data indicate that consolidation treatment with anti-CD137 mAbs might prevent MM relapse.
Subject(s)
4-1BB Ligand/metabolism , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Immunotherapy/methods , Multiple Myeloma/drug therapy , Animals , Antibodies, Monoclonal/therapeutic use , Antigens, Neoplasm/immunology , Antineoplastic Agents/therapeutic use , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Disease Models, Animal , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Knockout , Multiple Myeloma/pathology , T-Lymphocytes, RegulatoryABSTRACT
We propose a new approach for tumor immunotherapy which is based on a switching control strategy defined on domains of attraction of equilibria of interest. For this, we consider a recently derived model which captures the effects of the tumor cells on the immune system and viceversa, through predator-prey competition terms. Additionally, it incorporates the immune system's mechanism for producing hunting immune cells, which makes the model suitable for immunotherapy strategies analysis and design. For computing domains of attraction for the tumor nonlinear dynamics, and thus, for deriving immunotherapeutic strategies we employ rational Lyapunov functions. Finally, we apply the switching control strategy to destabilize an invasive tumor equilibrium and steer the system trajectories to tumor dormancy.
