Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-HodgkinLymphomas

Background: The drug Nivolumab has been approved to treat some cancers. Researchers want to see if it can slow the growth of other cancers. They want to study its effects on cancers that may have not responded to chemotherapy or other treatments. Objectives: To see if Nivolumab slows the growth of some types of cancer or stops them from getting worse. To test the safety of the drug. Eligibility: People 12 and older who have Epstein-Barr Virus (EBV)-positive lymphoproliferative disorders or EBV-positive non-Hodgkin lymphomas with no standard therapy Design: Participants will be screened with: Medical history Physical exam Blood and urine tests CAT scan of the chest, abdomen, and pelvis Tumor and bone marrow biopsies (sample taken) Magnetic resonance imaging scan of the brain Lumbar puncture (also known as spinal tap) Positron emission tomography/computed tomography scan with a radioactive tracer Every 2 weeks, participants will get Nivolumab by vein over about 1 hour. They will also have: Physical exam Blood and pregnancy tests Review of side effects and medications During the study, participants will repeat most of the screening tests. They may also have other biopsies. After stopping treatment, participants will have a visit every 3 months for 1 year. Then they will have a visit every 6 months for years 2-5, and then once a year. They will have a physical exam and blood tests.

BACKGROUND: * Epstein-Barr virus (EBV) is a chronic viral infection associated with a heterogeneous group of lymphoproliferative disorders (LPD) and non-Hodgkin lymphomas (NHL). * The shared pathobiology of EBV-positive LPDs and NHLs includes a defect in host mechanisms of immune tolerance and immunosurveillance. * Programmed death-1 (PD-1) is a surface protein present on T cells, B cells, and macrophages that serves a co-inhibitory role to negatively regulate immune responses * PD-1 and its ligands, PD-L1 and PD-L2, are overexpressed in EBV-positive lymphoproliferative disorders and are markers of aggressive behavior. * Blockade of the PD-1 pathway induces T-cell responses against tumor antigens in a variety of cancers, including Hodgkin lymphoma, that lead to clinical remissions. * Nivolumab is a fully human IgG4 monoclonal anti-PD-1 receptor antibody with clinical activity in both indolent and aggressive lymphomas. OBJECTIVE: -To determine the best overall response rate of nivolumab in subjects with EBV-positive LPD and EBV-positive NHL ELIGIBLITY: * Subjects must have a confirmed diagnosis of an EBV-positive LPD, or an EBV-positive NHL confirmed by Laboratory of Pathology, NCI --NOTE: LPD subjects may be previously untreated or relapsed from prior therapy; patients with EBV-positive B-cell NHL subjects must have relapsed from previous treatment with an anthracycline and rituximab-based regimen or be considered not eligible for the same * Adequate bone marrow function (unless disease-related) defined as: * Absolute neutrophil count \>= 750/mcL * Hemoglobin \>= 9g/dL (transfusion permitted) * Platelet count \>= 50,000/mcL (transfusion not permitted) * Age greater than or equal to 12 years \<TAB\> DESIGN: * Phase II study of subjects with EBV-positive LPD and EBV-positive NHL, both relapsed and untreated. * Subjects will be treated with nivolumab 480 mg IV every 4 weeks for up to 2 years if responding disease with clinical improvement and no unacceptable toxicity. * All responding subjects (CR, PR, or SD with clinical benefit) who subsequently relapse or progress within 1 year after discontinuation of study drug are eligible for re-treatment. * An optimal two-stage phase II trial design will be used to rule out a best overall response rate of 20%. If fewer than 3 of the first 17 subjects respond, the study would accrue no more subjects. * Subjects with both EBV-positive LPD and EBV-positive NHL will be enrolled on this protocol for a total of 37 evaluable subjects. In order to allow for inevaluable subjects and screen failures, the accrual ceiling will be set at 40 subjects.