Immunomodulators in Lymphoma

Lymphomas are highly heterogeneous tumors and different histologies are characterized by significant differences in biology. Despite the structural and molecular differences between lymphoma types, it is well recognized that the tumor microenvironment plays a critical role in the lymphoma survival and growth. Over the past few years, understanding of this notion has brought immunotherapy to the forefront of lymphoma treatment by targeting the tumor microenvironment in order to produce an effective anti-tumor response. Thus, the area of lymphoma therapy has changed dramatically within the past few years with the use of checkpoint inhibitors and more recently CAR T-cells. Remarkable results have been reported in some lymphoma types but responses vary significantly between different histologies. Future approaches will focus on combination strategies that will attack lymphoma cells in addition to activating immune responses. These strategies include combinations of different checkpoint blocking antibodies, combinations of checkpoint blocking antibodies with agonistic antibodies, immunomodulatory agents, small molecule inhibitors or CAR T-cells, and armored CAR T-cells. A number of clinical trials testing such combinations are currently under way. In this review, we discuss strategies to modulate the immune response in lymphoma. We specifically address the obstacles to effective activation of the immune system against malignant B-cells and review the current approaches that try to overcome these barriers.