CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

• INCLUSION CRITERIA:

• Diagnosis

• Participant must:

• Have pathology confirmed B cell ALL (not isolated to the testis or CNS),CML with ALL transformation, or high-grade lymphoma (e.g., Burkitt slymphoma, B-lymphoblastic lymphoma, diffuse large B-cell lymphoma,inclusive of low-grade lymphoma that has transformed to high gradedisease); and

• Have relapsed or been refractory after at least one standard chemotherapyregimen and at least one salvage treatment. Participants with Philadelphiachromosome + ALL must have failed prior tyrosine kinase inhibitor; and

• Be ineligible for allogeneic stem cell transplant (SCT), have refused SCT,or have recurred after SCT; and

• Have no evidence of graft-versus- host disease (GVHD) and have beenwithout immunosuppressive agents for at least 30 days prior to apheresis,if undergone prior allogeneic SCT; and

• Be unable to access (in a timely manner), ineligible for, or haverelapsed/failed after or not responded to a commercially available CD19CAR T-cell construct; and

• Have evidence of at least minimal residual disease or PET-avid disease (lymphoma) at the time of enrollment.

• CD22/CD19 expression

• CD19 must be detected on >15% of the malignant cells by immunohistochemistry or > 80% by flow cytometry.

• CD22 positivity must be confirmed.

• Age >= 3 years of age and <=39 years of age at time of enrollment.

• Clinical Performance status: Participants >= 16 years of age: Karnofsky >= 50%;Participants < 16 years of age: Lansky scale >= 50%.

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

• leukocytes >= 750/mcL*

• platelets >= 50,000/mcL*

• total bilirubin <=2 X ULN (except in the case of participants with documentedGilbert s disease > 3x ULN)

• AST(SGOT)/ALT(SGPT) <=10 x institutional upper limit of normal

• creatinine <= the maximum for age listed in the table below OR

• measured creatinine clearance >=60 mL/min/1.73 m^2 for participants withcreatinine levels above the max listed below per age.

• Age (Years) <= 5 || Maximum Serum Creatinine (mg/dL) <= 0.8

• Age (Years) 6 to <= 10 || Maximum Serum Creatinine (mg/dL) <= 1.0

• Age (Years) >10 || Maximum Serum Creatinine (mg/dL) <= 1.2

• a participant will not be excluded because of pancytopenia >= Grade 3if it is due to underlying bone marrow involvement by leukemia

• Central nervous system (CNS) Status

• Participants with leukemia with CNS 1 and 2 disease are eligible in the absence ofexclusion criteria

• Participants of child-bearing or child-fathering potential must be willing topractice effective birth control from the time of enrollment until 12 monthsfollowing completion of study treatment for women and for 4 months followingcompletion of study treatment for men.

• Participants who are breastfeeding or plan to breastfeed must agree todiscontinue/postpone breastfeeding while on study therapy and until 1 month afterthe administration of CAR.

• Cardiac function: Left ventricular ejection fraction >= 45% or fractional shortening >=28%

• Pulmonary Function

• Baseline oxygen saturation >92% on room air at rest

• Ability of participant or Legally Authorized Representative (LAR) to understand andthe willingness to sign a written informed consent document.

• Ability and willingness of participant or Legally Authorized Representative (LAR) toco- enroll on 15-C-0028: Follow-up Evaluation for Gene-Therapy Related DelayedAdverse Events after Participation in Pediatric Oncology Branch Clinical Trials.

EXCLUSION CRITERIA:

Participants meeting any of the following criteria are not eligible for participation in the study:

• Participants with CNS3 disease, neurologic signs of CNS disease, radiologicallydetected active CNS lymphoma

• Hyperleukocytosis (>= 50,000 blasts/microL)

• Positive serum or urine beta-HCG pregnancy test performed at screening.

• Participants will be excluded based on prior therapy if they fail to meet followingwashout criteria:

• Therapy: Systemic Chemotherapy, anti-neoplastic agents, antibody- basedtherapies

• Washout*: >=2 weeks

• Exceptions: 6 weeks for clofarabine or nitrosoureas; No washout for priorintrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increaseswithin prior 2 weeks) or ALL maintenance-type chemotherapy (vincristine, 6-mercaptopurine, oral methotrexate, or a tyrosine kinase inhibitor forparticipants with Ph+ ALL) provided there is recovery from any acute toxiceffects

• Therapy: Radiation

• Washout*: >=3 weeks

• Exceptions: No time restriction with radiation therapy if the volume of bonemarrow treated is less than 10% and the participant has measurable/evaluabledisease outside the radiation window

• Therapy: Allogeneic Stem Cell Transplant

• Washout*: >= 100 days since SCT; >= 30 days since completion ofimmunosuppression; >= 6 weeks since donor lymphocyte infusion (DLI)

• Exceptions: Cannot have evidence of active graft-versus-host disease (GVHD)

• Therapy: CAR T-Cell Therapy or other Adoptive Cell Therapy

• Washout*: > 30 days post infusion

• Washout: Time between therapy and apheresis

• Positive HIV antibodies consistent with active HIV.

• Positive hepatitis C antibodies or positive Hepatitis B surface antigen (HbsAG)indicative of current/active HCV/HBV.

• Active second malignancy other than in situ carcinoma of the cervix, unless thetumor was treated with curative intent at least two years previously and participantis in remission.

• History of severe, immediate hypersensitivity reaction attributed to compounds ofsimilar chemical or biologic composition to any agents used in study or in themanufacturing of the cells.

• Uncontrolled, symptomatic, intercurrent illness or social situations that wouldlimit compliance with study requirements or in the opinion of the PI would pose anunacceptable risk to the participant.