Harnessing the power of the immune system in non-Hodgkin lymphoma: immunomodulators, checkpoint inhibitors, and beyond.

Non-Hodgkin lymphoma is a malignancy of B lymphocytes that typically infiltrate sites of disease, including the lymph nodes, spleen, and bone marrow. Beyond the presence of malignant cells, many immune cells are also present within the tumor microenvironment. Although these immune cells have the potential to regulate the growth of malignant B cells, intratumoral immune cells are unable to eradicate lymphoma cells and most patients with lymphoma have clinical evidence of disease progression. Recent data have identified some of the mechanisms that account for the suppressed antitumor immune response and have created opportunities for treatment to overcome the deficiencies. Two general categories of immunological therapies are available. The first approach is to use agents that prevent inhibitory signals via immune checkpoint receptors that downregulate immune cell function. Blockade of suppressive programmed cell death 1 (PD-1) or CTLA-4 signaling has resulted in significant clinical activity by allowing intratumoral T cells to remain activated and target malignant cells. A second approach is to additionally activate T cells that are suboptimally active or suppressed, by providing signals through costimulatory molecules including CD27 or CD40 or by adding immunostimulatory cytokines. There has been significant heterogeneity in the responses to these treatment approaches. Clinical responses are seen in many diseases, but the most promising responses have been with PD-1 blockade in Hodgkin lymphoma. In other lymphomas, responses are seen but only in a subset of patients. Further research is needed to identify the mechanisms that account for response and to identify patients most likely to benefit from immune modulation.