CD19-CD34t Metabolically Programmed CAR T-Cell Therapy for the Treatment of Patients with CD19 Positive Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Small Lymphocytic Lymphoma

Inclusion Criteria

• Participants must have histologic confirmation of one of the following: * CD19+ aggressive non-Hodgkin lymphoma including any of the following subtypes: ** Diffuse Large B-cell lymphoma, not otherwise specified ** Diffuse large B-cell lymphoma (DLBCL), germinal-center B-cell type (GCB) ** DLBCL, activated B-cell type (ABC) ** T-cell histiocyte-rich B-cell lymphomas (THRBCL) ** Primary cutaneous DLBCL, leg type ** Intravascular large B cell lymphoma ** Epstein-Barr virus (EBV)+ DLBCL, not otherwise specified (NOS) ** DLBCL associated with chronic inflammation ** Human herpesvirus 8 (HHV8)+ DLBCL, NOS ** High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (double hit lymphoma) ** High grade B-cell lymphoma, NOS ** Primary mediastinal B-cell lymphoma ** B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Hodgkin lymphoma, as well as with features intermediate between DLBCL and Burkitt lymphoma ** Follicular lymphoma grade 3B ** Transformation of indolent lymphoma (i.e. CLL, marginal zone lymphoma [MZL], follicular lymphoma [FL], Waldenstrom’s lymphoma,etc) to diffuse large B-cell lymphoma ** Burkitt lymphoma ** Lymphomatoid granulomatosis * CD19+ indolent non-Hodgkin lymphoma including any of the following subtypes: ** Follicular lymphoma (grade 1-3A) ** Marginal zone lymphoma: Including splenic marginal zone lymphoma, nodal marginal zone lymphoma, and mucosa associated lymphoid tissue (MALT) lymphoma ** Waldenstrom’s Macrogloublinemia ** Nodular lymphocyte predominant hodgkin lymphoma (with documented CD19 expression) * Mantle cell lymphoma * Chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL)
• Aggressive lymphoma: patients will qualify if any of the following scenarios are met below (radiation does not count as a line of therapy) * Relapse or persistent disease after >= 2 lines of systemic therapy OR * Refractory disease or relapse within 12 months of completion of 1st line systemic therapy OR * Refractory disease or relapse >= 1 line of therapy but not a candidate for autologous stem cell transplant * Patients with Burkitt lymphoma will qualify after >= 1 line of therapy regardless of the timing of relapse
• Indolent lymphoma: Relapse or persistent disease after >= 2 lines of systemic therapy. (Neither single agent rituximab or radiation qualify as a line of therapy.)
• Mantle cell lymphoma: Relapse or persistent disease after >= 1 line of systemic therapy. Neither single agent rituximab or radiation qualify as a line of therapy
• Chronic lymphocytic leukemia/small lymphocytic lymphoma: Evidence of progression or intolerance after >= 2 lines of therapy. The following will qualify as a line of therapy for CLL/SLL: systemic chemoimmunotherapy (e.g. bendamustine and rituximab [BR], cyclophosphamide, fludarabine, rituximab [FCR], etc), bruton tyrosine kinase (BTK) inhibitor, B-cell lymphoma 2 (BCL-2) inhibitor, or PI3 kinase inhibitor. Neither single agent rituximab/obinutuzumab or radiation qualify as a line of therapy
• Participants must be at least 18 years old
• Participants must have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale
• Participants must have adequate caregiving support for CAR T-cell therapy as determined by the principal investigator (PI)/co-investigator (Co-I)
• Participants must have measurable disease on cross section imaging by PET-CT and/or CT scans alone that is at least 1.5 cm in the longest diameter and measurable in two perpendicular dimensions as defined by IWG criteria. If participants with CLL do not have measurable disease on imaging, a bone marrow biopsy showing >= 5% CLL involvement in the bone marrow will qualify for enrollment
• Participants that have received prior CD19 targeted therapy in the past they must have a tissue biopsy after completion of CD19 targeted therapy noting CD19 expression by either flowcytometry or immunohistochemistry (IHC). CD19 expression must be sufficient per PI/Co-I
• Platelet count >= 50,000 cells/mm^3 (unless directly attributable to disease within the bone marrow) (within 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 750 cells/mm^3 (unless directly attributable to disease within the bone marrow) (within 14 days prior to registration)
• Absolute lymphocyte count >= 150 cells/ mm^3 (unless directly attributable to disease within the bone marrow) (within 14 days prior to registration)
• Serum bilirubin =< 1.5 X upper limit of normal (ULN) unless attributed to Gilbert's syndrome or hemolysis or lymphoma involvement (within 14 days prior to registration)
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 3.0 x ULN or =< 5.0 x ULN unless attributed to lymphoma involvement (within 14 days prior to registration)
• No clinically significant electrocardiogram (ECG) findings per PI/Co-I
• Oxygen saturation > 90% on room air
• Serum creatinine =< 2 mg/dL or creatinine clearance (as estimated by Cockcroft Gault equation) >= 60 mL/min (within 14 days prior to registration)
• Participants with hepatitis B virus infection must have undetectable viral load and on suppressive therapy within 14 days prior to registration and no evidence of hepatitis B virus (HBV) related hepatic damage
• Participants with hepatitis C infection must have complete eradication therapy completed, have no evidence of hepatitis C virus (HCV) related damage and have undetectable viral load within 14 days of registration
• Participants with known human immunodeficiency virus (HIV)-infection must be receiving anti-retroviral therapy and have an undetectable viral load test within 14 days prior to registration
• Women of childbearing potential (WOCBP) should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment. All men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below. Females of childbearing potential (FCBP) must have negative serum or urine pregnancy within 7 days prior to registration. * Men with female partners who are of childbearing potential: Recommendations for male and partner to use at least two effective contraceptive methods, as described above, during the study
• Participants are able to understand and voluntarily sign consent prior to any study related assessments or procedures are performed
• CRITERIA FOR LEUKAPHERESIS:
• Negative pregnancy test within 7 days prior to collection in females of childbearing age
• Lymphoma therapy stopping rules prior to leukapheresis collection (all criteria must be met prior to proceeding with collection): * Systemic cytotoxic drugs must be stopped >= 2 weeks prior to cell collection * Systemic immune checkpoint therapy must be stopped >= 2 weeks prior to cell collection * Lenalidomide must be stopped >= 4 weeks prior to cell collection * Intrathecal Methotrexate must be stopped >= 7 days prior to cell collection * Other therapies (i.e., Oral anti-lymphoma therapies such as BTK inhibitors, BCL-2 inhibitors, etc) must be stopped at least 2 weeks or 5 half-lives prior to cell collection * Systemic steroids must have been stopped 7 days prior to cell collection (doses < 10 mg daily are allowed at the discretion of the PI/Co-I) * Radiation must have stopped >= 2 weeks prior to collection * Short acting growth factors (e.g., neupogen) must be stopped 5 days prior to cell collection. Long acting growth factors (e.g., neulasta) must be stopped 10 days prior to cell collection * Recommend following institutional guidelines for discontinuation of anti-lymphoma agents not specifically listed here
• Must have no evidence of a clinically significant uncontrolled infection prior to leukapheresis
• Absolute lymphocyte count (ALC) >= 150 cells/mm^3 within 48 hours prior to collection
• CRITERIA FOR LYMPHODEPLETING CHEMOTHERAPY:
• Negative pregnancy test within 7 days prior to starting lymphodepleting chemotherapy in females of childbearing age
• No evidence of uncontrolled infection or sepsis
• No clinically significant signs or symptoms of cardiac dysfunction defined as symptoms consistent with NYHA CHF classification III or IV
• No live vaccines within 6 weeks prior to lymphodepleting (LD) chemotherapy (chemo)
• If symptoms of central nervous system (CNS) disease have developed from the time of enrollment/collection, these symptoms should be investigated and resulted as negative prior to start of LD chemotherapy
• Recommend all labs appropriate per institutional guidelines to proceed with LD chemotherapy. This includes but is not limited to complete blood count (CBC), chemistries including sodium, potassium, chloride, total carbon dioxide (CO2), creatinine, glucose, urea nitrogen, albumin, alkaline phosphatase, ALT/serum glutamate pyruvate transaminase {SGPT}, AST/serum glutamic oxaloacetic transaminase (SGOT), total bilirubin
• Disease staging with imaging (i.e., PET-CT scan) and bone marrow biopsy to be performed in window according to calendar. It is strongly recommended that PET-CT scan is repeated prior to LD chemo if any systemic therapy or radiation therapy (ie bridging) has been received since the last disease staging
• Should an event exceed these criteria immediately prior to conditioning chemotherapy, conditioning chemotherapy must be delayed until the event resolves to =< grade 1 or baseline
• Lymphoma therapy stopping rules prior to starting lymphodepleting chemotherapy and CAR-T infusion: * Systemic IV chemotherapy or CD20 monoclonal antibody (Ab) or checkpoint inhibitors must be stopped >= 2 weeks prior to CAR-T infusion. Oral anti-lymphoma therapies (i.e. BTK inhibitors, BCL-2 inhibitors) must be stopped at least 2 weeks or 5 half-lives prior to LD chemo whichever is sooner * Recommend following institutional guidelines for discontinuation ofanti-neoplastic agents not specifically listed above * Any CNS disease prophylaxis must be stopped >= 2 weeks prior to CAR-T infusion * Non-CNS site of radiation must be completed >= 2 wks prior to planned CAR-T infusion; CNS directed radiation must be completed >= 8 wks prior to planned CAR-T infusion * Therapeutic systemic doses of steroids must be stopped >= 72 hrs prior to CAR-T infusion. Physiological replacement doses of steroids < 10 mg of prednisone daily or equivalent is allowed per discretion of PI/Co-I * Short acting growth factors (e.g., neupogen) must be stopped >= 5 days prior to CAR-T infusion. Long acting growth factors (e.g., neulasta) must be stopped >= 10 days prior to CAR T-cell infusion
• CRITERIA FOR CAR T-CELL INFUSION:
• CD19-CD34t metabolically programmed CAR T-cells must have met release criteria
• Therapeutic systemic doses of steroids must be stopped >= 72 hrs prior to CAR-T infusion. Physiological replacement doses of steroids < 10 mg of prednisone daily or equivalent is allowed per discretion of investigator. Other lymphoma stopping rules should be followed
• Subject has no evidence of hemodynamic instability
• Subject has not developed a new requirement for supplemental oxygen therapy
• Subject must be without symptomatic progression of disease after the start of lymphodepleting chemotherapy
• Subject must not have uncontrolled systemic fungal, bacterial, or viral infection
• There is no evidence of clinically significant cardiac dysfunction (defined as symptoms consistent with NYHA CHF classification III or IV), uncontrolled cardiac arrythmia, clinically significant tumor lysis syndrome, or acute neurological toxicity > grade 1 (with the exception of peripheral sensory neuropathy)
• Recommend all other labs appropriate per institutional guidelines to proceed with CAR T-cell infusion. This includes but is not limited to CBC, chemistries including sodium, potassium, chloride, total CO2, creatinine, glucose, urea nitrogen, albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, total bilirubin)
• Two doses of interleukin (IL)-6 blocking agents (i.e., tocilizumab) are available on-site for ordering by the bone marrow transplantation (BMT)/cellular therapy physician for each subject
• If these criteria are not met, measures will be taken to resolve the underlying condition(s) and cells infused upon subject recovery
• ELIGIBILITY CRITERIA FOR SUBSEQUENT CELL INFUSIONS:
• Cell infusion of CD19-CD34t metabolically programmed CAR T-cells has been deemed safe based on previous enrollment
• Response to previous infusion: Subjects who had a PR or SD with clinical benefit may elect to receive another infusion of cells. Subjects that initially had a CR may only receive a second dose if evaluable disease recurs. Clinical benefit is indicated by an improvement in the subject’s health status (e.g., disease control, improved performance status or quality of life, etc.)
• At least 60 days have passed since the previous cell infusion
• Any toxicity (regardless of causality) after the previous CD19-CD34t metabolically programmed CAR T-cell infusion must resolve such that subjects meet all the initial eligibility criteria
• The cell dose (based on CAR transduced cells) for the second infusion shall not be greater than the current dose level completed or the MTD if this has been determined. It also must be at least at dose level -1 to be infused
• Patients should have assessment of ongoing CD19 expression prior to CAR infusion by either flow cytometry or IHC with expression reviewed by PI/Co-I
• Prior to second infusion the study team will seek and obtain approval from the Food and Drug Administration (FDA) for a second infusion
• As a rule, subjects who incurred a dose limiting toxicity (DLT) after receiving the first cell infusion will not be eligible to receive additional cell infusions unless institutional review board (IRB), Data Safety Monitoring Committee (DSMC) and FDA approval is granted

Exclusion Criteria

• Women who are pregnant or breast-feeding
• Participants with active CNS lymphoma. Participants can have a history of active CNS lymphoma
• Participants with evidence of graft versus (vs) host disease from allogeneic stem cell transplant are ineligible unless it is either grade 1 involvement of the skin or not requiring systemic immunosuppression
• Participants with uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
• Participants with a history of stroke or intracranial hemorrhage within 6 months prior to registration. Any CNS disorder that would serve as a major barrier in evaluating neurotoxicity/ICANs per enrolling physician
• Participants with prior history of malignancy other than lymphoma unless subject is free of disease for more than 1 year from signing consent. Exceptions include the following: * Basal cell carcinoma of the skin * Squamous cell carcinoma of the skin * Carcinoma in situ of the cervix or breast * Previously treated localized prostate cancer with normal prostate specific antigen (PSA) levels
• Participants with primary immunodeficiency or history of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 1 year
• Participants with receipt of live vaccine within 28 days prior to registration
• Participants with history of autologous stem cell transplant within the last 60 days or allogeneic stem cell transplant within the last 90 days or CAR T-cell therapy within the last 180 days
• Participants with a history of severe immediate hypersensitivity reaction to any of the agents used in the study
• Participants with any other illness that in the opinion of the investigator, would exclude the patient from participating in this study
• Participants must not have evidence of active CNS lymphoma involvement. This includes parenchymal, spinal cord, meningeal, or cerebrospinal fluid involvement. Patients with history of CNS involvement must have documented remission by contrast-enhanced magnetic resonance imaging (MRI) imaging and cerebrospinal fluid (CSF) evaluation for at least 60 days prior to registration
• Patients must not have any unstable angina, or myocardial infarction within the last 6 months, or symptoms consistent with New York Heart Association (NYHA) congestive heart failure (CHF) classification III or IV