Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy for Chronic Lymphocytic Leukemia (CLL)

• INCLUSION CRITERIA:

• Malignancy criteria

• Histologically confirmed participants with either CLL or SLL will be eligible.

• Demonstration of CD19 expression on CLL/SLL, as assessed by the NCI Laboratoryof Pathology or NIH Department of Laboratory Medicine Hematopathology section.

• CD19 expression must be uniform meaning no populations of clearly CD19-negativeCLL/SLL cells are observed.

• Participants must have received prior systemic therapy. The last dosage ofsystemic therapy (including corticosteroids) must be at least 14 days prior tothe first dose of rituximab.

• For participants who have received antibodies targeting CD19, at least sixtydays must elapse between therapy with antibodies targeting CD19 and CAR T-cellinfusion.

• Participants must have received at least two prior treatment regimens at leastone of which must have contained a Bruton s tyrosine kinase (BTK) inhibitor.Participants who took a BTK inhibitor but stopped due to intolerance arepotentially eligible.

• All participants must have measurable malignancy as defined by at least one ofthe criteria below.

• Presence of CLL or SLL masses that are measurable (minimum 1.5 cm inlargest diameter) by CT scan is required unless bone marrow or bloodinvolvement with malignancy is detected. All masses must be less than orequal to 10.0 cm in the largest diameter.

• For CLL with only bone marrow and/or blood involvement, no mass isnecessary, but if a mass is not present, bone marrow and/or bloodmalignancy must be detectable by flow cytometry. Any level of CLLdetectable by flow cytometry is sufficient for enrollment.

• Other inclusion criteria:

• Age >= 18 years.

• Performance status (ECOG) 0-1.

• Participants must have adequate organ and marrow function as defined below:

• ANC >= 1,000/mcL without the support of filgrastim or other growth factorsin the 10 days prior to enrollment

• platelets >= 50,000/mcL without transfusion support

• hemoglobin >= 8 g/dL

• total bilirubin <= 2.0 mg/dL

• ALT or AST Serum ALT and AST less or equal to 3 times the upper limit ofthe institutional normal unless liver involvement by malignancy isdemonstrated. If liver involvement with malignancy is detected, ALT andAST must be less than or equal to 5 times the upper limit of normal

• Serum Creatinine Serum creatinine levels < 1.5 X institutional ULN.Participants with serum creatinine >= 1.5 X institutional ULN mayparticipate if serum creatinine eGFR is >=50 mL/min/1.73m^2 by 2021CKD-EPI equation.

• ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvictransaminase);

• AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetictransaminase); GFR=glomerular filtration rate; ULN=upper limit ofnormal.

• (A)Creatinine clearance (CrCl) or eGFR should be calculated perinstitutional standard.

• B cells must make up less than 90% of blood lymphocytes on a lymphocytephenotyping profile TBNK at the time of enrollment.

• Room air oxygen saturation of 92% or greater

• Participants of child-bearing or child-fathering potential must be willing topractice abstinence or highly effective contraception from the time ofenrollment on this study and for 12 months after receiving the protocoltreatment, or until CAR T cells are no longer detectable in the blood,whichever is later.

• Participants must agree not to donate eggs for 12 months after receiving theprotocol treatment, or until CAR T cells are no longer detectable in the blood,whichever is later.

• Participants who are breastfeeding must be willing to cease breastfeeding fromtime of enrollment until 6 months after receiving treatment, or until CAR Tcells are no longer detectable in the blood, whichever is later.

• Participants must have a negative blood PCR test for hepatitis B DNA. Ifhepatitis B DNA (PCR) testing is not available, participants must have anegative hepatitis B surface antigen and negative hepatitis B core antibodytest.

• Participants must have a negative blood PCR test for hepatitis C RNA. Only ifHepatitis C PCR testing is not available in a timely manner, participants musthave a negative Hepatitis C antibody test.

• Cardiac ejection fraction of greater than or equal to 50% by echocardiographyand no evidence of hemodynamically significant pericardial effusion asdetermined by an echocardiogram within 30 days prior to treatment start.

• All participants must have the ability to understand and willingness to sign awritten informed consent.

• All participants must be willing to undergo mandatory biopsies during thestudy. A bone marrow biopsy will be required prior to the chemotherapy and CART-cell infusion. Another bone marrow biopsy will be required approximately 14days after CAR T-cell infusion.

EXCLUSION CRITERIA:

• Participants who are receiving any other investigational agents.

• Participants who have had prior CAR T-cell therapy.

• Participants who have had a live-attenuated or viral vector-based vaccine in thelast 60 days prior to pre-leukapheresis rituximab. Participants who plan to receivea live attenuated or viral vector-based vaccine within the first 100 days after CART-cell infusion.

• Participants that require urgent therapy due to tumor mass effects or spinal cordcompression.

• Participants that have active hemolytic anemia.

• Current/active HIV infection, as measured by seropositivity for HIV antibody.

• Participants with second malignancies in addition to their CLL are not eligible ifthe second malignancy has required treatment with surgery, radiation orchemotherapy, or other therapies within the past 3 years or is not in completeremission. Exceptions are that, in the last 3 years, participants may have hadsuccessful resection of nonmetastatic basal cell or squamous cell carcinoma of theskin, and participants may have received hormonal therapy for fully resected breastcancer.

• Positive beta Human chorionic gonadotropin (Beta-HCG) serum or urine pregnancy testin women of childbearing potential (WOCBP) performed at screening.

• Active uncontrolled systemic infections (defined as infections causing fevers within 48 hours of the date of planned protocol rituximab or chemotherapy start andinfections requiring intravenous antibiotics when intravenous antibiotics have beenadministered for less than 72 hours at the time of protocol rituximab orchemotherapy start). There must be objective evidence of infection, including, butnot limited to, a positive blood, urine or sputum culture, positive nasal swab orblood test for viral infection, or the appearance of infiltrates on imaging of thelung.

• Active coagulation disorders or other major uncontrolled medical illnesses of thecardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary orimmune system, history of myocardial infarction, history of ventricular tachycardiaor ventricular fibrillation, active cardiac arrhythmias (Resolved atrialfibrillation that is not treated with anticoagulants is allowed.), activeobstructive or restrictive pulmonary disease, active autoimmune diseases such asrheumatoid arthritis.These include uncontrolled intercurrent illness manifesting aselectrolyte derangements or as assessed by chemistries.

• Significant neurologic disorders, including a history of a seizure disorder as anadult, that are not completely and permanently resolved and not requiring currenttreatment.

• Any form of primary immunodeficiency (such as Severe Combined ImmunodeficiencyDisease).

• Prior allogeneic stem cell transplant

• Systemic corticosteroid steroid therapy of any dose greater than 5 mg/day or more ofprednisone or equivalent is not allowed within 14 days prior to the first dose ofrituximab. Corticosteroid creams, ointments, and eye drops are allowed.

• Participants on systemic anticoagulant therapy except aspirin.

• History of severe immediate hypersensitivity reaction to any of the agents used inthis study, including hypersensitivity to aminoglycoside antibiotics, which may beused in the cell culture media.

• Active central nervous system/brain metastases or cerebrospinal fluid malignancy.

• Checkpoint inhibitor drugs such as pembrolizumab or nivolumab or other antibodiestargeting PD-1 or PDL-1 within 180 days of protocol enrollment. This is because ofpossible effects checkpoint inhibitor therapy could have on the participant's Tcells.

• Known active alcohol or drug abuse.

• History of allergy to study drug components.

• Active tumor lysis syndrome as assessed by serum uric acid, LDH, calcium, andphosphorus.

• Active rhabdomyolysis as assessed by elevated CK and acute change in renal functionas reflected by increased creatinine and blood urea nitrogen (BUN).

• Active diabetic ketoacidosis or hyperosmolar hyperglycemic state, as assessed byserum glucose. The urine will be tested for ketones if serum glucose is over 350mg/dL at screening.