The Highs and Lows of Immune-Checkpoint Blockade in Lymphoma

Immunologic approaches to treating patients with cancer have shown promise, and immune-checkpoint blockade has been particularly successful. In many solid tumors, the presence of intratumoral immune cells has been predictive of a response to therapy, and blockade of inhibitory signals that dampen an effective antitumor response has resulted in clinical benefit for patients. Lymphoid malignancies, including Hodgkin lymphoma and non-Hodgkin lymphoma, are cancers of the immune system, and in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Therefore, many of the immunologic lessons learned from solid tumors may not directly translate to lymphoid malignancies, and the mechanisms of effective antitumor responses in these diseases may be different. In Hodgkin lymphoma, for example, immune-checkpoint blockade has resulted in response rates of 65% to 75%. In contrast, in non-Hodgkin lymphoma, responses to immune-checkpoint blockade in phase II trials have been seen in fewer than 10% of patients, and the reasons for this substantial difference are largely unknown. Combination approaches are likely needed, particularly in the various subtypes of non-Hodgkin lymphoma, and combinations that include cytotoxic agents seem more effective than combinations of immunologic therapies. Successful therapeutic combinations in lymphomas may require an approach that simultaneously blocks inhibitory immune signals, provides direct activation of the immune response, and directly inhibits the malignant clone.