CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Children or Young Adults with Recurrent or Refractory CD19 Positive B Acute Lymphoblastic Leukemia

Inclusion Criteria

• In view of the principal investigator (PI) and the primary oncologist, there must be no available alternative curative therapies or subject has declined to pursue alternative therapy; and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, recurred after SCT, or have disease activity that prohibits SCT at the time of enrollment * Chemotherapy refractory disease in subjects with B-ALL is defined as progression or stable disease after two lines of therapies * Recurrence of disease after achieving a complete response (CR) * Subjects with persistent or relapsed minimal residual disease (MRD) (by flow cytometry, polymerase chain reaction [PCR], fluorescence in situ hybridization [FISH], or next generation sequencing) require verification of MRD positivity on two occasions at least 4 weeks apart * Subjects with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) subjects are eligible if they progressed, had stable disease or relapsed after two lines of therapy, including tyrosine kinase inhibitors (TKIs) * Subjects with recurrence of isolated central nervous system (CNS) relapse after achieving complete remission (CR); if relapsed with MRD, will require verification of MRD positivity on two occasions at least 4 weeks apart
• Subjects with lymphoma must have progressed, had stable disease (SD), or recurred after initial treatment regimens that include an anthracycline and an anti-CD20 monoclonal antibody; subjects who relapse >= 12 months after therapy should have progressed after autologous transplant or been ineligible for autologous transplant
• CD19 expression is required at any time since diagnosis; if patient has received anti-CD19 targeted therapy (i.e. blinatumomab), then CD19 expression must be subsequently demonstrated. CD19 expression must be detected on greater than 50% of the malignant cells by immunohistochemistry or >= 90% by flow cytometry; the choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each subject; in general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples
• Subjects who have undergone autologous SCT with disease progression or relapse following SCT will be eligible if all other eligibility criteria are met; subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, they are at least 100 days post-transplant, they have no evidence of active graft versus host disease (GVHD) and have been without immunosuppressive agents for at least 30 days
• Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy will be eligible if < 5% of circulating levels of CD3+ cells express the previous CAR by flow cytometry
• Must have evaluable or measurable disease; subjects with lymphoma must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma must be present; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives * Exceptions: ** There is no time restriction with regard to prior intrathecal chemotherapy (including [incl.] steroids) provided there is complete recovery from any acute toxic effects of such ** Subjects receiving hydroxyurea may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis ** Subjects who are on standard ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine or oral methotrexate) may be enrolled provided that chemotherapy is discontinued at least 1 week prior to apheresis ** Subjects receiving steroid therapy at physiologic replacement doses (=< 5 mg/day of prednisone or equivalent doses of other corticosteroids) only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis ** For radiation therapy: radiation therapy must have been completed at least 3 weeks prior to enrollment, with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the subject has measurable/evaluable disease outside the radiation port
• Toxicities due to prior therapy must be stable and recovered to =< grade 1 (except for clinically non-significant toxicities, such as alopecia, nutritional support measures, electrolyte abnormalities, or those not impacting the investigator’s ability to assess treatment emergent toxicities)
• NOTE: the first subject in the first dose cohort must be >= 18 years of age if an adult has not been treated at that dose cohort on the companion Stanford protocol “Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Adults with Recurrent or Refractory B Cell Malignancies” and undergone safety evaluation at day 28 without evidence of dose limiting toxicity (DLT)
• Subjects > 10 years of age: Karnofsky >= 50%; Subjects =< 10 years of age: Lansky scale >= 50%
• Absolute neutrophil count (ANC) >= 750/uL if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); a subject will not be excluded because of pancytopenia >= grade 3 if it is due to disease, based on the results of bone marrow studies
• Platelet count >= 50,000/uL if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); a subject will not be excluded because of pancytopenia >= grade 3 if it is due to disease, based on the results of bone marrow studies
• Absolute lymphocyte count >= 150/uL
• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 10 upper limit of normal (ULN) (unless elevated ALT/AST is attributed to leukemia or lymphoma involvement of the liver, in which case this criterion will be waived and not disqualify a patient)
• Total bilirubin =< 1.5 mg/dl, except in subjects with Gilbert’s syndrome
• Cardiac ejection fraction >= 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
• No clinically significant pleural effusion
• Baseline oxygen saturation > 92% on room air
• Creatinine: within age adjusted normal institutional limits: * Age =< 5 years - maximum serum creatinine 0.8 mg/dL * Age 5 years < age =< 10 years - maximum serum creatinine 1.0 mg/dL * Age > 10 years - maximum serum creatinine 1.2 mg/dL OR
• Creatinine clearance >= 60 mL/min/1.73 m^2 (as estimated by Cockcroft Gault equation) for subjects with creatinine levels above institutional normal
• CNS status * Subjects with ALL ** Subjects with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy: *** CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of white blood cells (WBCs) *** CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm: **** CNS 2a: < 10/uL red blood cells (RBCs); < 5/uL WBCs and cytospin positive for blasts **** CNS 2b: >= 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts **** CNS 2c: >= 10/uL RBCs; >= 5/uL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm * Subjects with lymphoma ** Subjects must have no signs or symptoms of CNS disease or detectable evidence of CNS disease on magnetic resonance imaging (MRI) at the time of screening; subjects who have previously been treated for CNS disease and who have the following CNS status will be eligible: *** CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs *** CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm: **** CNS 2a: < 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts; **** CNS 2b: >= 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts; **** CNS 2c: >= 10/uL RBCs; >= 5/uL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm
• Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
• Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative regimen; females of child-bearing potential must have a negative pregnancy test
• Ability to give informed consent; all subjects >= 18 years of age must be able to give informed consent; for subjects < 18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent; pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate

Exclusion Criteria

• Recurrent or refractory ALL limited to isolated testicular
• Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of >= 5/uL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia)
• Hyperleukocytosis (>= 50,000 blasts/uL) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy
• History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management; simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment; ongoing infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen [HBsAg] positive) or hepatitis C virus (anti hepatitis C virus [HCV] positive); a history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing
• CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that in the judgment of the investigator may impair the ability to evaluate neurotoxicity
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment, or have cardiac atrial or cardiac ventricular lymphoma involvement
• Subjects receiving anticoagulation therapy
• Any medical condition that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of study treatment
• History of severe immediate hypersensitivity reaction to any of the agents used in this study
• Women of child-bearing potential who are pregnant or breastfeeding; females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential
• In the investigator’s judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation
• May not have primary immunodeficiency or history of systemic autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years