B-Cell Activating Factor Receptor (BAFFR)-Based Chimeric Antigen Receptor T-Cells With Fludarabine and Cyclophosphamide Lymphodepletion for the Treatment of Relapsed or Refractory B-cell Hematologic Malignancies

Inclusion Criteria:

• PRE-REGISTRATION: Age ≥ 18 years

• PRE-REGISTRATION: Confirmed diagnosis of 1 of the following relapsed or refractoryB-cell hematologic malignancies: chronic lymphocytic leukemia/small lymphocyticlymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginalzone lymphoma (MZL), or large B cell lymphoma (LBCL) including Richter'stransformation from CLL/SLL

• For CD19+ B cell malignancies; relapsed or refractory disease is defined by oneof the following histopathology:

• Biopsy proven SLL or flow cytometry proven CLL; relapsed or refractorydisease is defined as:

• Demonstration of progressive or stable disease by positron emissiontomography/computed tomography (PET/CT) or computed tomography (CT)criteria according to the international workshop on chronic lymphocyticleukemia (iwCLL) 2018 criteria

• Biopsy proven B-cell non-Hodgkin lymphoma (NHL) of any histopathology (including Richter Transformation of CLL); relapsed or refractory diseaseis defined as:

• Demonstration of progressive or stable disease by PET/CT or CT criteria asthe best response to the most recent chemotherapy regimen according to therevised Lugano Response Criteria for Malignant Lymphoma

• PRE-REGISTRATION: Disease Specific prior lines of therapies below:

• For CLL/SLL, patients must have received ≥ two prior lines of therapy, and/or ≥ 6 months of second line prior BTK inhibition (e.g. ibrutinib or other such asacalabrutinib or zanubrutinib) and must have failed to respond to venetoclax orbe intolerant. Exception: Patients in stable disease (SD) or partial response (PR) with a known ibrutinib resistance mutation (BTK or phospholipase Cγ2) maybe included even if on ibrutinib therapy for less than 6 months

• These patients may or may not have received prior antibody directedagainst cluster of differentiation 20 (CD20).

• For Follicular Lymphoma, patients must have received ≥ two prior lines oftherapy, including an antibody directed against CD20.

• NOTE: Prior cluster of differentiation 19 (CD19) directed chimeric antigenreceptor T-cell therapy (CART) must have a 100-day washout period.

• For Mantle Cell Lymphoma, patients must have received ≥ two prior lines oftherapy, including an antibody directed against CD20, and a BTK inhibitor.

• NOTE: Prior CD19 directed CART must have a 100-day washout period.

• For Marginal Zone Lymphoma, patients must have received ≥ two prior lines oftherapy, including an antibody directed against CD20.

• NOTE: Prior CD19 directed CART must have a 100-day washout period.

• For Large B cell Lymphoma, patients must have received ≥ two prior lines oftherapy, including an antibody directed against CD20. Prior exposure to CD19directed CART will be allowed at the discretion of the Principal Investigator.

• NOTE: Prior failed CD19 directed CART must have a 100-day washout period

• For Richter's Transformation, patients must have received ≥two prior lines oftherapy, including an antibody directed against CD20.

• 100-day washout period starts from the date of the last prior CAR-T infusion.

• PRE-REGISTRATION: Measurable disease

• REGISTRATION: Positive BAFFR test

• REGISTRATION: Measurable disease

• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2

• REGISTRATION: Hemoglobin ≥ 9.0 g/dL (unless due to documented marrow involvementwith disease) obtained ≤14 days prior to registration

• REGISTRATION: Absolute neutrophil count (ANC) ≥ 1500/mm^3 (unless due to documentedmarrow involvement with disease) obtained ≤14 days prior to registration

• REGISTRATION: Platelet count ≥100,000/mm^3 (unless due to documented marrowinvolvement with disease) obtained ≤ 14 days prior to registration

• REGISTRATION: Total bilirubin ≤ 1.5 x upper limits of normal (ULN) (Subjects withGilbert's Syndrome may be included if their total bilirubin is ≤ 3.0 x ULN anddirect bilirubin ≤ 1.5 x ULN) obtained ≤ 14 days prior to registration

• REGISTRATION: Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 xULN (≤ 5 x ULN for patients with liver involvement) obtained ≤ 14 days prior toregistration

• REGISTRATION: Prothrombin time (PT)/international normalized ratio (INR) /activatedpartial thromboplastin time (aPTT) ≤ 1.5 x ULN OR if patient is receivinganticoagulant therapy and INR or aPTT is within target range of therapy obtained ≤ 14 days prior to registration

• Patients on a stable, maintenance regimen of anticoagulant therapy for ≥ 30days prior to registration may have PT/INR measurements > 1.5 X ULN if, in thejudgment of the investigator, the patient is suitable for the study

• REGISTRATION: Calculated creatinine clearance ≥45 ml/min using the Cockcroft-Gaultformula obtained ≤ 14 days prior to registration

• REGISTRATION: Negative pregnancy test done ≤ 7 days prior to registration, forpersons of childbearing potential only. If the urine test is positive or cannot beconfirmed as negative, a serum pregnancy test will be required

• REGISTRATION: Provide written informed consent understand and comply withprotocol-required study procedures

• REGISTARTION: Patients must have an ejection fraction (EF) of ≥ 45%

• REGISTRATION: Patients must have pulse ox measurements of > 92% on room air

• REGISTRATION: Willingness to provide mandatory blood specimens for correlativeresearch

• REGISTRATION: Willing to return to enrolling institution for study follow-up

Exclusion Criteria:

• PRE-REGISTRATION: Prior solid organ transplantation

• PRE-REGISTRATION: Unstable angina, clinically significant arrhythmia, or myocardialinfarction ≤ 6 months of prior to pre-registration, or grade 3 or higher pericardialeffusion at the time of pre-registration

• PRE-REGISTRATION: Prior anti-BAFF-R therapies

• PRE-REGISTRATION: Known contraindication to lymphodepleting (LD) chemotherapy

• PRE-REGISTRATION: Use of systemic antitumor therapy or investigational agent ≤ 14days, prior to pre-registration

• PRE-REGISTRATION: Receiving any other investigational agent which would beconsidered as a treatment for the BAFF-R

• PRE-REGISTRATION: Autologous HCT ≤ 60 days prior to pre-registration

• PRE-REGISTRATION: Uncontrolled intercurrent non-cardiac illness including, but notlimited to:

• Previous or concurrent malignancy

• Ongoing or active infection

• Psychiatric illness/social situations

• Dyspnea at rest due to complications of advanced malignancy or other diseasethat requires continuous oxygen therapy * Persons of childbearing potential whoare pregnant or breastfeeding

• Life Expectancy of < 6 weeks

• Persons requiring systemic corticosteroids (>10 mg prednisone or equivalent perday) and/or other immunosuppressive therapy. Patients are allowed to usetopical corticosteroids

• Any other conditions that would limit compliance with study requirements

• PRE-REGISTRATION: Detectable malignant cells from cerebrospinal fluid (CSF) ormagnetic resonance imaging (MRI) indicating brain metastases during screening, or ahistory of central nervous system (CNS) involvement by malignancy (CSF or imaging)with still active disease. Note: Patients with a history of CNS involvementresolving after treatment and without active disease will be considered eligible ifother inclusion criteria are met

• PRE-REGISTRATION: History of a seizure disorder, major cerebrovascularischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease withCNS involvement

• PRE-REGISTRATION: Radiation therapy ≤ 14 days prior to pre-registration

• PRE-REGISTRATION: Prior allogeneic hematopoietic stem cell transplant (HCT) in ≤ 6months prior to pre-registration; patients with active graft versus host disease (GVHD) will not be eligible regardless of duration from prior allogeneic HCT

• PRE-REGISTRATION: Human immunodeficiency virus (HIV) positive patients

• PRE-REGISTRATION: Subjects with New York Health Association (NYHA) class III orgreater heart failure

• REGISTRATION: Eligible for auto-HCT based on investigator judgement

• REGISTRATION: Presence of active bacterial, viral, or fungal infection that isuncontrolled, based on investigator judgment

• REGISTRATION: Patients with active hepatitis B or hepatitis C infections areexcluded from the study. Patients who are documented to be HIV positive or provenHIV infection from testing are ineligible for the study. Infectious disease testing (HIV-1, HIV-2, hepatitis C virus (HCV) antibody and polymerase chain reaction (PCR),hepatitis B virus (HBV) surface antigen, HBV surface antibody, HBV core antibody)performed ≤ 45 days prior to registration may be considered for subject eligibility

• REGISTRATION: Previous or concurrent malignancy, except basal cell or squamous cellskin carcinoma, adequately resected and in situ carcinoma of cervix, or a previousmalignancy that was completely resected and has been in remission for ≥ 5 yearsprior to registration

• REGISTRATION: Persons of childbearing potential who are pregnant or breastfeeding

• REGISTRATION: Life expectancy of < 6 weeks