Autologous CD19/CD22 Chimeric Antigen Receptor T-cells in Treating Patients with Recurrent or Refractory CD19 Positive B Acute Lymphoblastic Leukemia

Inclusion Criteria

• For B-ALL * Confirmed diagnosis of relapsed or refractory B-cell ALL of one of the following types: ** Chemotherapy refractory disease in subjects with B-ALL is defined as progression or stable disease after two lines of lines of therapies ** Recurrence of disease after achieving complete remission (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
• CD19 expression is required at any time since diagnosis; if patient has received anti-CD19 targeted therapy (i.e. blinatumomab or CD19-CAR T cell), the CD19 expression must be subsequently demonstrated; CD19 expression may be detected by immunohistochemistry or 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 stem cell transplantation (SCT) with disease progression or relapse following SCT are eligible; subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, they have no evidence of 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 must be at least 30 days post CAR infusion and have < 5% of CD3+ cells express the previous CAR if a validated assay is available
• Must have evaluable or measurable disease; 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 ** 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 or 5 half-lives (whichever is shorter) 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 apheresis, 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)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; or Karnofsky >= 60%
• Absolute neutrophil count (ANC) >= 750/uL * A subject will not be excluded because of pancytopenia >= grade 3 if it is felt by the investigator to be due to underlying leukemia/lymphoma
• Platelet count >= 50,000/uL * A subject will not be excluded because of pancytopenia >= grade 3 if it is felt by the investigator to be due to underlying leukemia/lymphoma
• Absolute lymphocyte count >= 150/uL * A subject will not be excluded because of pancytopenia >= grade 3 if it is felt by the investigator to be due to underlying leukemia/lymphoma
• Creatinine =< 2 mg/dL or creatinine clearance >= 60 mL/min
• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 10 upper limit of normal (ULN) (elevated ALT/AST associated with leukemia or lymphoma involvement of the liver will not disqualify a subject; only one value required for eligibility)
• 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), multigated acquisition (MUGA) or cardiac magnetic resonance imaging (MRI) (performed within 180 days or after most recent anthracycline based treatment or mediastinal radiation therapy [whichever is most recent])
• No clinically significant electrocardiogram (ECG) findings
• No clinically significant pleural effusion
• Baseline oxygen saturation > 92% on room air
• CNS status * Subjects with CNS involvement are eligible as long as there are no overt signs or symptoms that in the evaluation of the investigator would mask or interfere with the neurological assessment of toxicity
• 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 lymphodepletion regimen
• Must be able to give informed consent; subjects unable to give informed consent will not be eligible for this study

Exclusion Criteria

• History of malignancy, unless disease free for at least 3 years; at the discretion of the principal investigator, subjects in remission for 1-2 years prior to enrollment may be deemed eligible after considering the nature of other malignancy, likelihood of recurrence during one year following CAR therapy, and impact of prior treatment on risk of CD19/CD22-CAR T cells. Subjects in remission < 1 year are not eligible * Exception: Nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) is eligible * Hormonal therapy in subjects in remission > 1 year will be allowed
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled; simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
• Known history of infection with any of the following: * Human immunodeficiency virus (HIV) * Hepatitis B (hepatitis B surface antigen [HBsAg] positive) * 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 PCR and/or nucleic acid testing
• Presence of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any 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
• Any medical condition that in the judgement of the 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 who are pregnant or breastfeeding
• In the investigators 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
• Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years