huCART19-IL18 Cells for the Treatment of Relapsed or Refractory CD19+ Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Acute Lymphoblastic Leukemia

Inclusion Criteria

• Signed informed consent form
• Documentation of CD19 expression on malignant cells by flow cytometry/immunohistochemistry (IHC) from a Clinical Laboratory Improvement Act (CLIA) certified laboratory * NHL patients: Within 6 months of physician-investigator confirmation of eligibility as long as there has been no intervening CD19 directed therapy since expression confirmed. Results outside of this window may be used, if there is no accessible tumor site and the subject did not receive intervening CD19 directed therapy since CD19 expression was confirmed * CLL and ALL patients: At time of most recent relapse. If the subject has subsequently received CD19-directed therapy since this result was obtained, repeating testing must be performed to determine eligibility
• Patients with relapsed disease after prior allogeneic stem cell transplant (SCT) must meet the following criteria: * Have no active graft versus host disease (GVHD) and require no immunosuppression. * Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility
• Creatinine =< 1.6 mg/dl
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3x upper limit of normal range
• Direct bilirubin =< 2.0 mg/dl, unless the subject has Gilbert’s syndrome (=< 3.0 mg/dl)
• Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygen > 92% on room air
• Left ventricle ejection fraction (LVEF) >= 40% confirmed by ECHO/MUGA
• Evidence of active disease. This could include circulating disease in the blood, disease in the bone marrow by standard morphology, or in non-Hodgkin lymphoma (NHL) patients, measurable disease per Lugano criteria
• Male or female age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1
• Subjects of reproductive potential must agree to use acceptable birth control methods
• NHL Patients (Cohorts A and D): * Patients with any of the following diagnoses: diffuse Large B-cell lymphoma not otherwise specified (DLBCL NOS), germinal center or activated B-cell types; primary cutaneous DLBCL; primary mediastinal (thymic) large B-cell lymphoma; ALK+ anaplastic large B-cell lymphoma; high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (i.e. “double or triple hit”); high-grade B-cell lymphoma, NOS; T-cell rich B-cell lymphoma; transformed follicular lymphoma; or any aggressive B-cell lymphoma arising from indolent lymphoma ** Patients must have either relapsed after, or be ineligible for, prior CAR T cell therapy, and meet one of the following criteria: *** Relapsed/refractory disease after at least 2 prior lines of appropriate therapy *** Relapsed/refractory disease after autologous SCT *** Relapsed/refractory disease after allogeneic SCT * Follicular lymphoma ** Patients who have received at least 2 prior lines of appropriate therapy (not including single agent monoclonal antibody therapy) and progressed within 2 years after second or higher line of therapy * Mantle cell lymphoma ** Patients must have either failed or be ineligible for standard of care Tecartus (brexucabtagene autoleucel) or other investigational CAR T cell product; and ** Patients must also meet one of the following criteria: *** Relapsed/refractory disease after at least 2 prior lines of appropriate therapy, including a BTK inhibitor. Single-agent monoclonal antibody therapy does not count towards prior lines of therapy *** Relapsed/refractory disease after prior autologous SCT *** Relapsed/refractory disease after prior allogeneic SCT
• CLL Patients (Cohort B): * Patients with relapsed/refractory disease after at least 2 prior lines of appropriate therapy * Patients must have previously received, or be intolerant to an approved BTK inhibitor and venetoclax, unless a BTK inhibitor or venetoclax is contraindicated * Large cell transformation of CLL (Richter’s transformation) ** Patients must be primary refractory or received at least 1 prior line of treatment for Richter’s Transformation
• ALL Patients (Cohorts C and D): * Patients with b-cell acute lymphoblastic leukemia. * Note: Chronic myeloid leukemia (CML) lymphoid blast crisis is considered a sub-type of relapsed B-ALL, thus will be encompassed in our definition of B-ALL throughout; AND * Patients with 2nd or greater relapse or refractory disease as defined by one of the following criteria: ** Recurrent disease in the blood or bone marrow identified morphologically, by IHC or flow; OR ** Isolated CNS disease. Note: Patients with prior/current history of CNS3 disease will only be eligible for treatment if the central nervous system (CNS) disease is responsive to therapy; OR ** Recurrent extramedullary disease at other (non-CNS) sites if disease response can be assessed radiographically. Note: Patients with recurrent extramedullary disease do not need to have detectable blood or bone marrow involvement; OR ** Any relapse after allogeneic SCT; OR ** Patients with refractory disease as defined by one of the following: *** Failure to achieve remission (<5% bone marrow blasts or ongoing extramedullary or CNS disease) after 2 cycles of induction chemotherapy; OR *** Patients that achieve remission but remain minimal residual disease (MRD)+ after ≥ 2 cycles of induction chemotherapy.
• ELIGIBILITY FOR RETREATMENT
• Subjects must have a manufactured huCART19-IL18 product available which meets the minimum acceptable dose for infusion * Note: Subjects without an adequate cryopreserved product available may still be considered for retreatment if determined clinically appropriate by the physician-investigator, however additional manufacturing would be required. This will require a written request to the sponsor for approval to allow for additional manufacturing
• Subjects must not have developed new disease complications, deterioration in performance status or overall clinical condition, new laboratory abnormalities, or new toxicities of therapy (either leukemia/lymphoma therapy or lymphodepleting chemotherapy) that would, in the opinion of the treating investigator, render it unsafe to proceed with CAR T cell infusion. The following are specific conditions that warrant delaying CAR T cell infusion: * Pulmonary: New requirement for supplemental oxygen or presence of radiographic abnormalities that are concerning for impending pulmonary decompensation. Chest imaging is not required to evaluate for radiographic abnormalities in the absence of suggestive symptoms or exam findings * Cardiac: New cardiac arrhythmia not controlled with medical management. Electrocardiogram (EKG) is not required to evaluate for arrhythmia in the absence of suggestive symptoms or exam findings * Hypotension requiring vasopressor support * Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48 hours of CAR T cell infusion
• Subjects must have received recommended prophylaxis and adhered to all required restrictions on pre-infusion therapy
• Subjects of child-bearing potential must not be pregnant as assessed by a negative serum beta human chorionic gonadotropin (HCG) test drawn within 14 days prior to the huCART19-IL18 retreatment infusion, and prior to the first day of lymphodepleting chemotherapy (as applicable)
• Subjects must undergo a respiratory virus panel (RVP) within 14 days prior to the planned CAR T cell retreatment infusion and prior to receipt of lymphodepleting chemotherapy (as applicable). If the subject is positive for influenza, Tamiflu or equivalent, should be administered per package insert. The subject must complete treatment prior to receiving lymphodepleting chemotherapy (as applicable) and CAR T cells. The RVP does not need to be repeated prior to the CAR T cell infusion; however, if influenza signs and symptoms are present, the CAR T cell retreatment infusion should be delayed until the subject is asymptomatic. If the subject is positive for another virus on the RVP, the lymphodepleting chemotherapy and CAR T cell retreatment infusion will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop. If clinical symptoms develop, the lymphodepleting chemotherapy and CAR T cell infusion will be delayed until resolution of these symptoms

Exclusion Criteria

• Active hepatitis B, active hepatitis C, or other active, uncontrolled infection
• Class III/IV cardiovascular disability according to the New York Heart Association Classification
• Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility
• Active acute or chronic GVHD requiring systemic therapy
• Dependence on systemic steroids or immunosuppressant medications
• Receipt of prior huCART19 therapy
• CNS disease as defined by disease-cohort as follows: * NHL/CLL Patients: Active CNS disease. Note: Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement. * ALL Patients: CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
• Pregnant or nursing (lactating) women
• Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, and unrelated to their cancer or previous cancer treatment
• Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to >= 10 mg of prednisone. Patients with autoimmune neurologic diseases (such as multiple sclerosis [MS]) will be excluded