Enhancing the efficacy of car T cell therapy in multiple-myeloma (MM) by blockade of immunosuppressive pathways in the tumor microenvironment

Despite a remarkable advancement in treatment, multiple-myeloma (MM) remains an incurable disease and novel approaches continue to be a priority. The interest in developing CAR T cell therapy for MM has dramatically increased over the last few years. Several CAR designs have been developed for specific redirection of T cells to reject MM cells, few of which have reached clinical testing. In contrast to high efficacy of CAR therapy in preclinical MM models which are based mostly on engrafted immunodeficient mice, the response to treatment in humans has been in most cases only partial and transient. This is likely to be associated with a tumor-induce immunosuppressive milieu that fosters immune escape. We hypothesize that neutralization of inhibitory pathways in the tumor microenvironment may exhibit therapeutic synergy and improve antitumor efficacy of CAR T cells against MM. An immunosuppressive role of T cell-associated inhibitory receptors such as PD-1 was demonstrated in MM and blocking these receptors has been suggested as a strategy to improve the outcome of immunotherapy for this disease. Myeloid-derived suppressor cells (MDSCs) represent additional major components of the tumor-promoting immunosuppressive MM microenvironment in humans. MDSCs are increased in MM patients and have bidirectional interaction with tumor and immune-effector cells. Both preclinical and clinical studies suggest that inhibition of MDSCs can efficiently augment MM-directed therapies.

Our preliminary data show that in an immunocompetent mice model of MM only a transient tumor regression can be achieved by MM-directed CAR T cells. Using this model we evaluate strategies to enhance the efficacy of CAR T cell therapy and extend the duration of response focusing on blockade of inhibitory receptors and suppressor cells.