There is evidence of expression of PD-L1 and/or PD-L2 in a subset of non-Hodgkin lymphomas as well as in the tumor microenvironment, making this pathway a promising target (51). as well as promising ongoing studies for dual antibody molecules, Dual-Affinity Re-Targeting (DART) proteins. This review highlights these three immunotherapy classes for relapsed/refractory non-Hodgkin lymphomas and discusses the mechanism of action, clinical efficacy, and toxicities of each. Keywords: Adoptive immunotherapy, antibodies, bispecific, lymphoma, non-Hodgkin, programmed cell death 1 receptor, antagonists, inhibitors Introduction The native immune system prevents and combats malignancy. The intact immune system recognizes tumor cells as foreign and inhibits progression by signaling CD4+/CD8+ T cells to target tumor cells (1,2). Unfortunately, tumors escape immune surveillance through alterations in surface antigen expression or presentation leading to decreased immune recognition. Tumors may convert naive/effector T cells into senescent T cells, which induce immune tolerance (3). Additional tumor evasion mechanisms include the expression of immunosuppressive cytokines or up-regulation of negative co-stimulatory molecules for T cells (1). A paradigm shift has occurred in cancer research from using cytotoxic chemotherapy to strategies aimed at amplifying and targeting immune response. Among the first therapies to demonstrate the power of the immune system was allogeneic stem cell transplant for hematologic malignancy. The donor provides non-malignant hematopoietic cells, and additionally T-cells. The donor T-cells target the recipients residual malignant cells and produce a beneficial graft versus tumor (GVT) effect. Depletion of these T cells from the donor product prior to transplant increases rates of relapse (4). An effective strategy to prevent early relapse following allogeneic hematopoietic stem cell transplant is withdrawal of immunosuppression, which unleashes the functionality of donor T cells (5). Donor lymphocyte infusions (DLIs) can successfully treat relapsed disease and further demonstrate the potency of the GVT effect (6). The benefit of allogeneic transplants is limited by the lack of specificity of donor T FLT3-IN-4 cells for residual malignant cells. Donor T cells also target healthy recipient tissue, leading to serious multi-organ toxicity known as graft-versus-host disease (GVHD) (7). To utilize the power of the immune system without the adverse effects of GVHD, work has been ongoing for 20 years in vaccinations against specific tumor antigens to bolster the immune system. The proposed technique uses a cancer vaccine as adjuvant therapy to lower the risk of relapse by boosting immune response to tumor (8). In follicular lymphoma (FL), patient-specific tumor-derived antigens in first remission may improve disease-free survival (9,10). Antibody therapies have further revolutionized the field of lymphoma, with rituximab, a monoclonal antibody to CD20, greatly improving outcomes when added to cytotoxic chemotherapy. FLT3-IN-4 Chemo-immunotherapy is now the first-line standard of care for many sub types of lymphoma (11). Treatment with chemo-immunotherapy for aggressive lymphomas such as diffuse large B-cell (DLBCL) obtains complete responses (CRs) in 75C80% of patients (12,13). However, the prognosis remains poor in patients who relapse or have refractory disease. The options for salvage therapy include high dose chemotherapy followed by autologous stem cell transplant (AHSCT) with response rates of only 63%. Patients who relapse within 12 months of first-line therapy have a particularly poor prognosis with a COL12A1 3-year progression-free survival (PFS) of only 23% with salvage therapy (14). Indolent non-Hodgkin lymphomas, such as FL, are slowly progressive but incurable. Despite rituximab-based regimens, 20% of FL patients relapse within 2 years of treatment. These patients have substantially increased risk of death with decreasing responsiveness to conventional rituximab-based therapies (15). Given the limited salvage options, non-Hodgkin lymphoma would benefit FLT3-IN-4 from the further application of immunotherapy. Adoptive cellular therapies, immune-checkpoint inhibitors, and novel antibody therapies have all demonstrated efficacy in both aggressive and indolent non-Hodgkin lymphoma. We will review the mechanism of action, clinical trial results, and toxicity management of the leading immunotherapies for treatment of non-Hodgkin lymphoma. Adoptive cellular therapy CAR T cells-mechanism CAR T cells are autologous T lymphocytes genetically engineered to bind to specific antigens expressed on malignant cells. Through the CAR T cell binding to the malignant cell, the signaling domains stimulate T-cell proliferation, cytolysis, and cytokine secretion to eliminate the tumor cell. CAR T cells are generated through apheresis of patients peripheral blood mononuclear cells at steady state. T cells are isolated from peripheral blood and activated. The T cells are then transduced.