RATIONALE: Biological therapies, such as agatolimod sodium, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving agatolimod sodium together with rituximab and yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of agatolimod sodium when given together with rituximab and yttrium Y 90 ibritumomab tiuxetan and to see how well it works in treating patients with recurrent or refractory non-Hodgkin lymphoma.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of CpG 7909 that can be delivered in four doses (days 6, 13, 20, 27) for patients with relapsed CD20+ non-Hodgkin's lymphoma. (Phase I) II. To assess the toxicity of CpG 7909 when combined with rituximab and Y-90 Zevalin in patients with lymphoma. (Phase I) III. To assess the overall response rate (CR + PR) of this regimen in relapsed diffuse large B cell lymphoma. (Phase II) IV. To assess the toxicity of the treatment regimen in patients with relapsed diffuse large B cell lymphoma. (Phase II) V. To assess the time to progression and duration of response in patients with relapsed diffuse large B cell lymphoma. (Phase II)

SECONDARY OBJECTIVES:

I. To report the response rate (complete remission + complete remission unconfirmed + partial remission) in this patient population after CpG 7909, rituximab, and Y-90 Zevalin. (Phase I) II. To compare the biodistribution of In-111 Zevalin radioimmunoconjugate scans before and after CpG 7909. (Phase I) III. To determine the HAMA/HACA rate in patients treated with this regimen. (Phase I) IV. To determine if CpG 7909 when given in the context of rituximab and Y-90 Zevalin can stimulate immune effector cells in the blood and tumor tissue. (Phase I)

OUTLINE:

This is a dose escalation study of agatolimod sodium followed by a phase II study.

PHASE I (patients with relapsed, refractory, or residual CD20+ non-Hodgkin lymphoma [closed to accrual as of 10/29/07]): Patients receive rituximab IV on days 1, 8 and 15, agatolimod sodium IV over 2 hours on days 6, 13, 20, and 27, and yttrium Y 90 ibritumomab tiuxetan* IV over 10 minutes on day 15 in the absence of disease progression and unacceptable toxicity.

*NOTE: Patients receive indium In 111 ibritumomab tiuxetan IV over 10 minutes on days 1 and 8. Patients undergo whole-body gamma camera imaging, single-photon emission computed tomography/CT scans, and blood sampling after each dose of indium In 111 ibritumomab tiuxetan to determine biodistribution. If biodistribution is acceptable, patients receive yttrium Y 90 ibritumomab tiuxetan.

PHASE II (patients with relapsed, refractory, or residual diffuse large B-cell lymphoma): Patients receive agatolimod sodium at the MTD as determined in phase I. Patients receive rituximab and yttrium Y 90 ibritumomab tiuxetan as in phase I.

*NOTE: Patients receive indium In 111 ibritumomab tiuxetan IV over 10 minutes on day 8. Patients undergo whole-body gamma camera imaging and blood sampling after each dose of indium In 111 ibritumomab tiuxetan to determine biodistribution.

After completion of study treatment, patients are followed periodically for up to 5 years.

Inclusion Criteria:

• The following histologic types by REAL classification and International Working Formulation (IWF) when applicable (NOTE: Closed to accrual as of 10/29/07): Small lymphocytic lymphoma; Lymphoplasmacytoid lymphoma; Follicular center lymphoma, follicular grades 1, 2, and 3; Extranodal marginal zone B cell lymphoma of MALT type; Nodal marginal zone B cell lymphoma
• The following histologic types by REAL classification and International Working Formulation (IWF) when applicable: Diffuse large cell; Transformed lymphoma
• Less than 25% bone marrow involvement of cellular marrow with lymphoma as determined by bilateral bone marrow aspirate and biopsy (the percent involvement should be estimated by the hematopathologist using all of the biopsy material)
• There is no limit on the number of prior therapies (patients who have previously received rituximab are eligible)
• Bi-dimensionally measurable disease: The patients must have >= 1 lesion that has a single diameter of >= 2 cm
• Absolute neutrophil count >= 1500/mm^3
• Platelet count >= 150,000
• Total lymphocyte count < 5000/mm^3 only for patients with small lymphocytic lymphoma
• HGB >= 8
• Biopsy-proven relapsed, refractory, or residual CD20+ non-Hodgkin's lymphomas; previous biopsies =<6 months prior to treatment on this protocol will be acceptable as long as there has not been intervening therapy; if the patient has received therapy for NHL between the time of the last biopsy and this protocol, then a re-biopsy is necessary
• ECOG performance status (PS) 0, 1, or 2
• Expected survival >= 3 months
• Willingness to provide all biologic specimens as required by the protocol
• Total bilirubin =< 2 x ULN mg/dL (if abnormal, direct bilirubin =< 1.5 x ULN)

Exclusion Criteria:

• Prior myeloablative therapies with autologous or allogeneic bone marrow transplantation or peripheral blood stem cell support
• Prior radioimmunotherapy including Y-90 Zevalin or 131-Iodine anti-B1 antibody or Lym-1
• Presence of CNS lymphoma
• Serious non-malignant disease such as active infection or other condition which in the opinion of the investigator would compromise other protocol objectives
• Major surgery other than diagnostic surgery =< 4 weeks prior to registration
• Another active primary malignancy
• Known HAMA/HACA (Human anti-mouse or anti-chimeric antibodies)
• Myelodysplastic syndrome or marrow chromosomal changes suggesting myelodysplasia
• 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], surgical sterilization, abstinence, etc.)
• Failed stem cell collection
• Marrow cellularity =< 15% (as determined on all bone marrow samples)
• Known to have lymphoma related to HIV or AIDS (these patients are excluded because it is unknown what effects prolonged B-cell depletion will have on these patient's immune system)
• G-CSF or GM-CSF therapy =< 1 week prior to study registration (pegylated filgrastim =< 3 weeks)
• Myelosuppressive chemotherapy =< 3 weeks prior to study registration (=< 6 weeks if rituximab, nitrosourea, or Mitomycin C)
• Skin rash (such as Stevens-Johnson's syndrome or toxic epidermal necrolysis) with prior rituximab therapy should not be entered on this study because of the risk of reoccurrence of that skin toxicity
• Abnormal renal function (serum creatinine > 2 mg/dL)
• Pre-existent clinical autoimmune or antibody mediated diseases, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, and autoimmune thrombocytopenia (patients that have no clinical symptoms of these diseases, but merely have previously detected antibodies are eligible)
• Received prior external beam radiation therapy to > 25% of active bone marrow
• Corticosteroid therapy at the time the patient enters the protocol; patients using prednisone or its equivalent for adrenal failure or using < 20mg of prednisone/day for other benign causes are accepted