Follicular lymphoma (FL) is a subtype of non-Hodgkin lymphoma that is incurable with conventional therapy. Yet a majority of patients can be cured by stem cell transplantation (SCT), the success of which depends primarily on the donor’s immune system. This demonstrates that FL is a very immune-sensitive disease. However, the toxicity of SCT is too high to justify its routine use, and while other forms of immunotherapy have been used in FL, none have yielded sufficiently frequent and durable responses. There is tremendous interest in oncology in monoclonal antibodies (mAbs) that target various immune checkpoints. Immune checkpoints are normally used by the body to regulate immune responses but can be usurped by tumors in order to shield themselves from immune attack. Several checkpoint mAbs have already been tested in FL patients that have relapsed or that have disease that is refractory to conventional treatment (R/R FL). Though this approach showed a favorable safety profile, there were durable responses only in a minority of patients. This suggests that FL may rely on immune checkpoints to survive but has anti-immunity shields that are too complex to be effectively disabled by single checkpoint mAbs. It is likely that multiple immune checkpoints are used by FL cells to evade the immune system. We seek to identify safe and effective immunotherapy approaches in FL by simultaneously targeting multiple checkpoint pathways and therefore propose a clinical trial of combination checkpoint immunotherapy in FL. This trial will sequentially test combinations of checkpoint mAbs, targeting three different immune checkpoints (PD-1, 4-1BB, and Ox-40), in conjunction with rituximab administered for just 6 months to patients with R/R FL. Those combinations that meet pre-defined success criteria will also be tested in patients with previously untreated FL. The clinical goal of this trial is to identify, within 30 months, promising short-duration combination treatment regimens in both R/R and untreated FL that can then be further tested in larger clinical trials. In addition, we will characterize in detail the immune landscape in patients receiving these treatments, to investigate how this relates to treatment response and resistance. The understanding gained through this study may allow the identification of markers of treatment sensitivity, the design of future combinations, and the successful treatment of FL with safe and effective immunotherapy.