Fourth-gen CAR T Cells Targeting CD19/CD22 for Highly Resistant B-cell Lymphoma/Leukemia (PMBCL/CNS-BCL).

Inclusion Criteria:

• Diagnosis: ALL In view of the PI and the primary oncologist, there must be noavailable alternative curative therapies or subject has declined to pursuealternative therapy; and subjects must be either ineligible for allogeneic stem celltransplant (SCT), have refused SCT, recurred after SCT, or have disease activitythat prohibits SCT at the time of enrollment.

• Chemotherapy refractory disease in subjects with B-ALL is defined as progression orstable 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 flowcytometry, PCR, FISH, or next generation sequencing) require verification of MRDpositivity 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 twolines of therapy, including tyrosine kinase inhibitors (TKIs).

• Subjects with recurrence of isolated CNS relapse after achieving complete remission (CR); if relapsed with MRD, will require verification of MRD positivity on twooccasions at least 4 weeks apart.

• Diagnosis: Lymphoma Subjects with lymphoma must have progressed, had SD, or recurredafter initial treatment regimens that include an anthracycline and an anti CD20monoclonal antibody. Subjects who relapse ≥12 months after therapy should haveprogressed after autologous transplant or been ineligible for autologous transplant.

• CD19 expression CD19 expression is required at any time since diagnosis. If patienthas received anti-CD19 targeted therapy (i.e. Blinatumomab), then CD19 expressionmust be subsequently demonstrated. CD19 expression. must be detected on greater than 50% of the malignant cells by immunohistochemistry or ≥ 90% by flow cytometry. Thechoice of whether to use flow cytometry or immunohistochemistry will be determinedby what is the most easily available tissue sample in each subject. In general,immunohistochemistry will be used for lymph node biopsies, flow cytometry will beused for peripheral blood and bone marrow samples.

• Subjects who have undergone autologous SCT with disease progression or relapsefollowing SCT will be eligible if all other eligibility criteria are met. Subjectswho have undergone allogeneic SCT will be eligible if, in addition to meeting othereligibility criteria, they are at least 100 days post-transplant, they have noevidence of active 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 beeligible if < 5% of circulating levels of CD3+ cells express the previous CAR byflow cytometry.

• Must have evaluable or measurable disease; subjects with lymphoma must haveevaluable or measurable disease according to the revised IWG Response Criteria forMalignant Lymphoma[66] must be present. Lesions that have been previously irradiatedwill be considered measurable only if progression has been documented followingcompletion of radiation therapy.

• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since anyprior systemic therapy at the time the subject is planned for leukapheresis, exceptfor systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5half-lives.

• Exceptions:

• There is no time restriction with regard to prior intrathecal chemotherapy (incl.steroids) provided there is complete recovery from any acute toxic effects of such;g. Subjects receiving hydroxyurea may be enrolled provided there has been noincrease in dose for at least 2 weeks prior to starting apheresis; h. Subjects whoare on standard ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine ororal methotrexate) may be enrolled provided that chemotherapy is discontinued atleast 1 week prior to apheresis.

• Subjects receiving steroid therapy at physiologic replacement doses (≤ 5 mg/day ofprednisone or equivalent doses of other corticosteroids) only are allowed providedthere has been no increase in dose for at least 2 weeks prior to starting apheresis;j. For radiation therapy: Radiation therapy must have been completed at least 3weeks prior to enrollment, with the exception that there is no time restriction ifthe volume of bone marrow treated is less than 10% and also the subject hasmeasurable/evaluable disease outside the radiation port.

• Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (exceptfor clinically non-significant toxicities, such as alopecia, nutritional supportmeasures, electrolyte abnormalities, or those not impacting the investigator'sability to assess treatment emergent toxicities)

• Age Greater than or equal to 1 year of age and less than or equal to 30 years of ageat time of enrollment; must meet parameters for apheresis per institutionalguidelines. NOTE: The first subject in the first dose cohort must be ≥ 18 years ofage if an adult has not been treated at that dose cohort on the companion Stanfordprotocol "Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR)T Cells in Adults with Recurrent or Refractory B Cell Malignancies" and undergonesafety evaluation at Day 28 without evidence of DLT.

• Performance Status: Subjects > 10 years of age: Karnofsky ≥ 50%; Subjects ≤ 10 yearsof age: Lansky scale ≥ 50% (See Appendix B Section 14.2)

• Normal Organ and Marrow Function (supportive care is allowed per institutionalstandards, i.e. filgrastim, transfusion)

• ANC ≥750/uL*

• Platelet count ≥50,000/uL*

• Absolute lymphocyte count ≥150/uL*

• Adequate renal, hepatic, pulmonary and cardiac function defined as:

• Serum ALT/AST ≤10 ULN (unless elevated ALT/AST is attributed to leukemia or lymphomainvolvement of the liver, in which case this criterion will be waived and notdisqualify a patient).

• Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome.

• Cardiac ejection fraction ≥ 45%, no evidence of physiologically significantpericardial effusion as determined by an ECHO, and no clinically significant ECGfindings

• No clinically significant pleural effusion

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

• creatinine: within age adjusted normal institutional limits (see table below) OR

• creatinine clearance ≥60 mL/min/1.73 m2 (as estimated by Cockcroft Gault Equation)for subjects with creatinine levels above institutional normal.

• Age (Years) Maximum Serum Creatinine (mg/dL)

-≤5 0.8 5 < age ≤ 10 1.0 >10 1.2

• if these cytopenias are not judged by the investigator to be due to underlyingdisease (i.e. potentially reversible with anti-neoplastic therapy); A subject willnot be excluded because of pancytopenia ≥ Grade 3 if it is due to disease, based onthe results of bone marrow studies.

• CNS Status

• Subjects with ALL

• Subjects with the following CNS status are eligible only in the absence ofneurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

• CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospinpreparation, regardless of the number of WBCs;

• CNS 2, defined as presence of < 5/µL WBCs in CSF and cytospin positive for blasts,or > 5/µL WBCs but negative by Steinherz/Bleyer algorithm:

CNS 2a: <10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts; CNS 2b: ≥10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts; CNS 2c: ≥10/µL RBCs; ≥5/µL 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 CNSdisease on MRI at the time of screening. Subjects who have previously been treatedfor 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 cytospinpreparation, regardless of the number of WBCs;

• CNS 2, defined as presence of < 5/µL WBCs in CSF and cytospin positive for blasts,or > 5/µL WBCs but negative by Steinherz/Bleyer algorithm:

• CNS 2a: < 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;

• CNS 2b: ≥ 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;

• CNS 2c: ≥ 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts but negative bySteinherz/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 postmenopausalfor at least 2 years are not considered to be of childbearing potential)

• Contraception Subjects of child-bearing or child-fathering potential must be willingto 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 because ofthe potentially dangerous/unknown effects on the fetus.

• Ability to give informed consent. All subjects ≥ 18 years of age must be able togive informed consent. For subjects <18 years old their legal authorizedrepresentative (LAR) (i.e. parent or guardian) must give informed consent. Pediatricsubjects will be included in age appropriate discussion and verbal assent will beobtained for those > 7 years of age, when appropriate.

Exclusion Criteria:

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

• Recurrent or refractory ALL limited to isolated testicular.

• Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of ≥ 5/µL WBCs in CSF and cytospin positive for blasts [in the absence of a traumaticlumbar puncture] and/or clinical signs of CNS leukemia).

• Hyperleukocytosis (≥ 50,000 blasts/µL) or rapidly progressive disease that in theestimation of the investigator and sponsor would compromise ability to completestudy 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 orrequiring IV antimicrobials for management. Simple UTI and uncomplicated bacterialpharyngitis are permitted if responding to active treatment.

• Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study will poseunacceptable risk. A history of hepatitis B or hepatitis C is permitted if the viralload is undetectable per quantitative PCR and/or nucleic acid testing.

• CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellardisease, or autoimmune disease with CNS involvement that in the judgment of theinvestigator 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, orhave cardiac atrial or cardiac ventricular lymphoma involvement.

• Subjects receiving anticoagulation therapy.

• Any medical condition that in the judgement of the principal investigator is likelyto interfere with assessment of safety or efficacy of study treatment

• History of severe immediate hypersensitivity reaction to any of the agents used inthis study.

• Women of child-bearing potential who are pregnant or breastfeeding because of thepotentially dangerous effects of the conditioning lymphodepletion chemotherapy onthe fetus or infant. Females who have undergone surgical sterilization or who havebeen postmenopausal for at least 2 years are not considered to be of childbearingpotential.

• In the investigator's judgment, the subject is unlikely to complete allprotocol-required study visits or procedures, including follow-up visits, or complywith 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 orrequiring systemic immunosuppression/systemic disease modifying agents within thelast 2 years.