This phase II clinical trial studies the combination of mosunetuzumab and polatuzumab vedotin in order to see how well it works in patients with untreated follicular lymphoma. Mosunetuzumab is an antibody that has been engineered to attach to two target cells in the immune system: T cells that normally perform tasks like killing virus-infected cells, and cancerous B cells. Mosunetuzumab has been designed to direct these T cells to kill the cancerous B cells instead. Polatuzumab vedotin is an antibody-drug conjugate that attaches to certain cancerous B cells and then delivers a drug specifically to those cells.

Inclusion Criteria:

• Diagnosis of follicular lymphoma grade 1-3A, stage II-IV by Ann Arbor criteria.

• One or more of the following criteria (adapted from GELF criteria):

  • Any nodal or extranodal tumor mass with diameter > 7 cm
  • Involvement of at least 3 nodal sites, each with diameter > 3 cm
  • Presence of any systemic or B symptoms
  • Splenic enlargement with inferior margin below the umbilical line
  • Compression syndrome (e.g., ureteral, orbital, gastrointestinal)
  • Pleural or peritoneal serous effusion (irrespective of cell content)
  • Cytopenia(s) attributable to lymphoma

• At least 18 years of age.

• ECOG performance status ≤ 2

• Adequate hematologic and organ function (unless due to underlying lymphoma per the investigator; see below), defined as follows:

  • Absolute neutrophil count ≥ 1,000/mcL
  • Platelets ≥ 75,000/mcL
  • Hemoglobin ≥ 8 g/dL
  • Serum total bilirubin ≤ 1.5 x IULN (or ≤ 3 x IULN for patients with Gilbert syndrome)
  • AST(SGOT)/ALT(SGPT) ≤ 3 x IULN
  • Serum creatinine ≤ 1.0 x IULN or creatinine clearance ≥ 50 mL/min by Cockcroft-Gault

• Patients with extensive bone marrow involvement by lymphoma and/or disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled if the following criteria are met:

  • Absolute neutrophil count ≥ 500/mcL
  • Platelet count ≥ 50,000/mcL without platelet transfusion within 14 days prior to the first dose of mosunetuzumab
  • Hemoglobin ≥ 7 g/dL without red blood cell transfusion within 7 days prior to the first dose of mosunetuzumab

• The effects of mosunetuzumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study treatment, for 3 months following the final dose of mosunetuzumab, for 9 months after the final dose of polatuzumab vedotin, and for 3 months after the final dose of tocilizumab, as applicable. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study treatment, for 6 months after the final dose of polatuzumab vedotin, and for 2 months after the final dose of tocilizumab, as applicable.

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Prior history of aggressive B cell lymphoma such as diffuse large B cell lymphoma or high-grade B cell lymphoma.

• Known history of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents.

• Known history of macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH).

• Current or past history of CNS lymphoma.

• Any prior systemic therapy for follicular lymphoma.

• Treatment with radiotherapy within 2 weeks prior to the first dose of mosunetuzumab (otherwise one measurable lesion outside of the radiation field must remain).

• Treatment with any anti-CD20 monoclonal antibody within 4 weeks of Day 1 of Cycle 1.

• Current or recent history (within the last 6 months) of CNS disease, such as stroke, epilepsy CNS vasculitis, or serious progressive neurodegenerative disease, with clinically significant symptoms.

• Treatment with systemic immunosuppressive medications, including but not limited to prednisone (> 20 mg), azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents within 2 weeks prior to Day 1 of Cycle 1.

  * Note: The use of inhaled corticosteroids, mineralocorticoids for management of orthostatic hypotension, and single dose dexamethasone for nausea or B symptoms is permitted.

• History of solid organ transplantation.

• History of allogeneic stem cell transplantation.

• Prior treatment with chimeric antigen receptor T cell therapy within 30 days before Day 1 of Cycle 1.

• History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine monoclonal antibodies (mAbs).

• Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the mosunetuzumab formulation, including mannitol.

• History of erythema multiforme, Grade ≥ 3 rash, or blistering following prior treatment with immunomodulatory derivatives.

• Known active bacterial, viral, fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 1 week of Day 1 of Cycle 1.

• Known or suspected chronic active Epstein-Barr virus (EBV) infection.

• Current Grade > 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease.

• Active hepatitis B infection.

  * Patients who are hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (HBcAb) positive, must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation

• Active hepatitis C infection.

  * Patients who are positive for hepatitis C virus (HCV) antibody must be negative for HCV by PCR to be eligible for study participation

• Known history of human immunodeficiency virus (HIV) positive status.

• History of progressive multifocal leukoencephalopathy (PML).

• Administration of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study.

  * Patients must not receive live, attenuated vaccines (e.g., FluMist®) while receiving study treatment or after the last dose until B cell recovery to the normal ranges.

• Other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of the following:

  • Any of the following malignancies previously curatively treated: carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the breast, basal, or squamous cell skin cancer
  • Stage I melanoma, low grade, early stage localized prostate cancer, or any other previously treated malignancy that has been in remission without treatment for at least 2 years prior to enrollment

• Active autoimmune disease requiring treatment.

• History of autoimmune disease, including, but not limited to, myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

  • Patients with a remote history of, or well-controlled autoimmune disease, with a treatment free interval from immunosuppressive therapy for 12 months may be eligible to enroll if judged to be safe by the investigator.
  • Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible.
  • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
  • Patients with a history of disease-related immune thrombocytopenic purpura, or autoimmune hemolytic anemia may be eligible.

• Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to, significant cardiovascular disease (e.g., New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) or significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm).

• Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1 Day 1 or anticipation of a major surgical procedure during the course of the study.

• Pregnant or lactating or intending to become pregnant during the study.

  * Women of childbearing potential must have 1 negative serum pregnancy test result (minimum sensitivity, 25 mIU/mL) within 7 days of initiating Cycle 1 Day 1 of therapy.

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results.