Mass General - Division of Clinical Research

Subjects must satisfy the following criteria to be enrolled in the study: 1. Age ≥ 18 years at the time of informed consent. 2. Signed written informed consent obtained prior to any study procedure. 3. Willing and able to adhere to the study visit schedule and other protocol requirements. 4. Relapsed and/or refractory aggressive B-cell NHL as defined: 1. Histologically confirmed DLBCL not otherwise specified, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (HGBCL), transformed DLBCL from follicular (tFL) or marginal zone lymphoma (tMZL), primary mediastinal B-cell lymphoma (PMBCL), or FL grade 3b (FL3B) (Note: Subjects with Richter's transformation (transformed DLBCL from CLL) are ineligible) AND 2. Have relapsed and/or refractory disease after at least 2 lines of systemic therapy which must include at least one anthracycline and rituximab (or other anti-CD20 monoclonal antibody). Note: Lines of therapy will exclude those given for prior indolent lymphoma. It is not required for subjects to have had anthracycline for their DLBCL if received for indolent disease AND/OR 3. Have relapsed and/or refractory DLBCL failed to ASCT treatment. Note: ASCT failure is defined as either failure to achieve an objective response (PR or better), or disease progression after ASCT(Note: Subjects who were not candidates to receive ASCT treatment (due to age or other factors) are eligible; the reason for not receiving ASCT must be documented in the electronic case report form (eCRF). 5. Positron emission tomography (PET)-positive disease as per the Lugano Classification (at screening or following bridging therapy, whichever is later). 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Adequate organ function as detailed in the protocol. 8. Adequate vascular access for leukapheresis. 9. Willing and able to undergo tumor biopsies (in subjects with accessible disease). 10. Agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals as detailed in the protocol. 11. Female and male subjects agree to use effective contraception as detailed in the protocol.

The presence of any of the following will exclude a subject from enrollment: 1. Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or unwillingness or inability to follow the procedures required in the protocol. 2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 3. Any condition that confounds the ability to interpret data from the study. 4. Central nervous system (CNS)-only involvement by malignancy (note: subjects with pathologically-confirmed secondary CNS involvement are allowed).) 5. Prior CAR T- cell or genetically-modified T- cell therapy, or prior CD19- targeted therapy (including, but not limited to, anti-CD19 mAbs or bispecific antibodies).) 6. Treatment with the following therapies or procedure within the specified period: 1. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 14 days before leukapheresis administration. Physiologic replacement, topical, and inhaled steroids are permitted. 2. Cytotoxic chemotherapeutic agents (eg, doxorubicin, vincristine, gemcitabine, oxaliplatin, carboplatin, etoposide) within 7 days of leukapheresis, with the exception of alkylating agents. 3. Intrathecal therapy (eg, dexamethasone, methotrexate, cytosine arabinoside, cytarabine) within 7 days of leukapheresis. 4. Oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 5 half-lives have elapsed prior to leukapheresis. 5. Alkylating agents (eg, cyclophosphamide, ifosfamide, bendamustine) within 4 weeks of leukapheresis. 6. Any experimental therapy within 8 weeks (for biologics) or 5 half-lives (for small molecules) before leukapheresis 7. Immunosuppressive therapies within 4 weeks of leukapheresis (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, immunosuppressive antibodies such as anti-TNF, anti-IL6, or anti-IL6R) 8. Monoclonal antibodies (including rituximab, polatuzumab, etc.) within 7 days. 9. Donor lymphocyte infusions within 6 weeks of leukapheresis 10. Radiation within 6 weeks of leukapheresis. Subjects must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated PET-positive lesions are present, is allowed up to 14 days prior to leukapheresis. 11. Autologous stem-cell transplant (SCT) (ie, Day 0 receipt of hematopoietic stem cells) within 3 months of leukapheresis 12. Washout of prior therapy (eg, bridging therapy for disease control) 7. Active autoimmune disease requiring immunosuppressive therapy. 8. Allogenic SCT (ie, Day 0 receipt of hematopoietic stem cells) within 6 months of leukapheresis or presence of ongoing symptoms or treatment for chronic graft-versus host disease (GVHD).) 9. Hypersensitivity to fludarabine and/or cyclophosphamide. 10. Prior history of malignancies, other than studied NHL, unless the subject has been free of the disease for ≥ 2 years except for the following non-invasive malignancies: 1. Basal or squamous cell carcinoma of the skin 2. Carcinoma in situ of the cervix or the breast 3. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM (tumor, nodes, metastasis) clinical staging system) or prostate cancer that is curative 4. Other completely resected stage 1 solid tumor with low risk for recurrence 11. Active hepatitis B, hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening. 12. Uncontrolled or active systemic fungal, bacterial, viral or other infection despite appropriate anti-infection treatment at the time of leukapheresis or pre-treatment evaluation. 13. History of any one of the following cardiovascular conditions within the 6 months prior to screening: Class III or IV heart failure as defined by the New York Heart Association, myocardial infarction, unstable angina, angioplasty or stenting, or other clinically significant cardiac disease. 14. History or presence of clinically significant CNS pathology such as seizure disorder, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, or cerebellar disease. Presence of clinically active psychosis. 15. History of ≥ Grade 2 hemorrhage within 30 days of screening. 16. Pregnant or nursing (lactating) women. 17. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to leukapheresis or initiation of LD chemotherapy. -Acute symptoms must have resolved and based on investigator assessment in consultation with the Sponsor Medical Monitor, there are no sequelae that would place the subject at a higher risk of receiving study treatment. 18. Previous SARS-CoV-2 vaccine within 14 days prior to leukapheresis or initiation of LD chemotherapy.