PRIMARY OBJECTIVES: I. To characterize the safety profile of MDX-010 (ipilimumab) monoclonal antibody and identify a tolerable immunologically active dose level in B cell lymphoma patients. II. To evaluate the clinical response rate in B cell lymphoma patients treated with MDX-010. SECONDARY OBJECTIVES: I. To evaluate the phenotype and function of memory T cells before and after treatment with MDX-010 by: * Quantitation and phenotypic characterization of peripheral blood and tumor infiltrating T-cells, including cluster of differentiation (CD)4+CD25+ regulatory T cells. * Measurement of tumor-specific T cells in peripheral blood lymphocytes. * Measuring proliferation of memory T cells in response to recall antigens (tetanus toxoid and keyhole limpet hemocyanin \[KLH\]). II. Measurement of anti-tumor antibodies in serum pre- and post-therapy. III. To evaluate the time to progression. IV. To evaluate the duration of response to treatment with MDX-010. OUTLINE: This is a multicenter, open-label, phase I, dose-escalation study followed by a phase II study. Patients are grouped according to prior treatment with a vaccine therapy for lymphoma (yes vs no). PHASE I: Patients receive anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) IV over 90 minutes on day 1. Treatment repeats every 28 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 6 patients from each group receive escalating doses of MDX-010 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. PHASE II: Patients receive MDX-010 as in phase I at the MTD. Patients are followed at 1 and 4 months and then every 6 months for up to 2 years.
Inclusion Criteria: * Histologic proof of recurring or residual follicular B-cell non-Hodgkin's lymphoma (grade I or II), by Revised European American Lymphoma Classification (REAL) or World Health Organization (WHO) classifications which has relapsed or persisted after 3 or fewer conventional therapies, including chemotherapy or monoclonal antibody therapy; note: all patients with previously treated B-cell lymphomas of any histology with the exception of small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL) are eligible * Tumor measurable by computed tomography (CT) scans (at least one pathologic node measuring 2.0 x 2.0 cm, or 2 nodes measuring \> 1.5 x 1.5 cm after collection of tumor for immunologic analyses) * At least one prior treatment regimen but no more than 3 prior chemotherapy regimens; patients previously treated with monoclonal antibodies or radiotherapy to a single site will be eligible; these therapies will be considered prior treatment regimens but will not be considered as prior chemotherapy; tumor vaccines will not be counted as prior therapies, as all such agents are investigational * Absolute neutrophil count (ANC) \>= 1000/uL * Platelets (PLT) \>= 75,000/uL * Total bilirubin =\< 1.5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST) =\< 3 x upper limit or normal (ULN) * Creatinine =\< 1.5 x ULN * Hemoglobin \>= 8 g/dL * Ability to provide informed consent * Willingness to return to the Mayo Clinic Rochester or the University of California, Los Angeles for follow up * Life expectancy \>= 24 weeks * Willingness to provide all biologic specimens as required by the protocol Exclusion Criteria: * Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, 3, or 4 * Any uncontrolled infection, hepatitis C virus (HCV)+ (unless HCV ribonucleic acid \[RNA\]-negative by polymerase chain reaction \[PCR\]) or hepatitis B surface antigen (HBsAg)+, or human immunodeficiency virus (HIV) positive patients or patients with known immune deficiency states * Previous MDX-010 therapy regardless of interval since last treatment * Prior treatment with fludarabine or 2-chlorodeoxyadenosine =\< 12 months prior to registration * Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment * New York Heart Association classification III or IV or a history of angina pectoris requiring active treatment * Clinical evidence of central nervous system involvement by lymphoma * Any of the following: * Pregnant women * Nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device \[IUD\], or abstinence, etc.) * Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration \[FDA\]-approved indication and in the context of a research investigation) * Diagnosis of small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL) * Any requirement for concurrent steroid therapy, including use of inhaled steroids for asthma * History of autoimmune disease requiring systemic therapy with immunosuppressive drugs, including but not limited to rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, or psoriasis * Antinuclear antibody (ANA) titer or rheumatoid factor titer \> 3x institutional ULN
is designated in this study