Scientific rationale for immunotherapy in lymphoma and predictors of response

The immune system plays a fundamental role in lymphoma biology, and early studies with anti-CD20 monoclonal antibodies exploited this phenomenon by demonstrating activity either alone or in combination with chemotherapy in B-cell non-Hodgkin lymphoma (B-NHL). More recently, immune checkpoint blockade encompassing the PD-1/PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways as a form of active immuno-therapy in lymphoma has been discovered. The engagement of the PD-1 receptor to its ligand (PD-L1/PD-L2) on lymphoma cells blocks T-cell receptor signalling and T-cell response leading to T-cell exhaustion (immune escape). Similarly, CTLA-4, a negative regulator of T-cell activation, dampens antitumor immune responses. Blockade of the in-teractions of PD-1 and PD-L1 is a rational therapeutic approach, and pidilizumab, nivolumab and pembrolizumab have been studied and characterized in Hodgkins and non-Hodgkins lymphoma. Immune co-stimulatory agents and vaccines are also being ex-plored. In this review, data for all passive and active immunotherapy strategies in lymphoma from anti-CD20 monoclonal antibodies and the immunomodulatory agent lenalidomide to checkpoint inhibitors, co-stimulatory agents [e.g., anti-CD137 (urelumab, MEDI6469)] and vaccines will be presented. Information pertaining to CD19 chimeric antigen receptor T-cell (CAR-T), a cellular therapy that represents an exciting approach with impressive response rates in B-cell NHL, will also be discussed. Lastly, predictive biomarkers and tools available for the assessment of response to such therapies will be summarized.