CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells With or Without NKTR-255 in Adults With Recurrent or Refractory B Cell Malignancies

For B acute lymphoblastic leukemia (ALL)

1. Confirmed diagnosis of relapsed or refractory B-cell ALL of one of the followingtypes:

• Chemotherapy refractory disease in subjects with B-ALL, defined as progressionor stable disease after one line of therapy.

• Recurrence of disease after achieving CR.

2. 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.

3. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL)subjects are eligible if they progressed after receiving a tyrosine kinase inhibitor (TKI).

4. 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.

5. CD19 positive expression- CD19 expression is required at any time since diagnosis.If patient has received anti-CD19 targeted therapy (i.e. Blinatumomab or CD19-CAR Tcells), then CD19 expression must be subsequently demonstrated. CD19 expression maybe detected by immunohistochemistry or by flow cytometry. The choice of whether touse flow cytometry or immunohistochemistry will be determined by what is the mosteasily available tissue sample in each subject. In general, immunohistochemistrywill be used for lymph node biopsies, flow cytometry will be used for peripheralblood and bone marrow samples.

6. Subjects who have undergone autologous SCT with disease progression or relapsefollowing SCT are eligible. Subjects who have undergone allogeneic SCT will beeligible if, in addition to meeting other eligibility criteria, they have elelinoevidence of GVHD and have been without immunosuppressive agents for at least 30days.

7. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy must be atleast 30 days post CAR infusion and may not have eficence of persistnce of CAR Tcells in blood smples (circulating levels of genetically modified cels of >/= 5% byflow cytometry.

8. Must have evaluable or measurable disease. Lesions that have been previouslyirradiated will be considered measurable only if progression has been documentedfollowing completion of radiation therapy.

9. 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:

10. There is no time restriction with regard to prior intrathecal chemotherapy (incl. steroids) provided there is complete recovery from any acute toxiceffects;

11. Subjects who are on standard ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine or oral methotrexate) may be enrolled provided thatchemotherapy is discontinued at least 1 week or 5 half-lives (whichever isshorter) prior to apheresis.

12. Subjects receiving steroid therapy at physiologic replacement doses (≤5 mg/dayof prednisone or equivalent doses of other corticosteroids) only are allowedprovided there has been no increase in dose for at least 2 weeks prior tostarting apheresis;

13. For radiation therapy: Radiation therapy must have been completed at least 3weeks prior to apheresis, with the exception that there is no time restrictionif the volume of bone marrow treated is less than 10% and also the subject hasmeasurable/evaluable disease outside the radiation port.

14. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (exceptfor clinically non-significant toxicities such as alopecia)

15. Age 18 or older

16. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; orKarnofsky ≥ 60%

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

18. ANC ≥ 1000/uL*

19. Platelet count ≥ 50,000/uL*

20. Absolute lymphocyte count ≥ 300/uL*

21. Adequate renal, hepatic, pulmonary and cardiac function defined as:

22. Creatinine ≤ 2 mg/dL or creatinine clearance ≥ 60 mL/min

23. Serum ALT or AST ≤ 5x ULN (Elevated ALT/AST associated with leukemia orlymphoma involvement of the liver will not disqualify a subject; only one valuerequired for eligibility).

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

25. Cardiac ejection fraction ≥ 45%, no evidence of physiologically significantpericardial effusion as determined by an ECHO, MUGA or Cardiac MRI [performedwithin 180 days or after most recent anthracycline based treatment ormediastinal radiation therapy (whichever is most recent)]

26. No clinically significant ECG findings

27. No clinically significant pleural effusion

28. Baseline oxygen saturation > 92% on room air * A subject will not be excludedbecause of cytopenia if it is felt by the investigator to be due to underlyingleukemia/lymphoma.

29. Subjects with CNS involvement are eligible as long as there are no overt signs orsymptoms that in the evaluation of the investigator would mask or interfere with theneurological assessment of toxicity.

30. 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)

31. Subjects of child-bearing or child-fathering potential must be willing to practicebirth control from the time of enrollment on this study and for four (4) monthsafter receiving the preparative lymphodepletion regimen or 1 month after the lastdose of NKTR_255, whichever is later.

32. Ability to give informed consent. Must be able to give informed consent. Subjectsunable to give informed consent will not be eligible for this study.

=ELIGIBILITY TO RECEIVE NKTR-255=

• Received a CD19/CD22 CAR-T infusion

• No persisting grade ≥1 CRS or greater than grade 1 fever within 12 hours precedingNKTR-255 infusion

• No grade 4 CRS within 96 hours preceding NKTR-255 infusion

• No persisting grade ≥ 2 neurotoxicity on the day of NKTR-255 infusion

• No previous grade ≥ 3 neurotoxicity of > 48 hours duration at any time precedingNKTR-255 infusion

• ANC ≥ 1000/µL

• No intervention with tocilizumab and/or dexamethasone within 48 hours precedingNKTR-255 infusion

• No active, serious, and uncontrolled infection(s)

• No contraindications according to the PI's assessment

• Life expectancy > 30 days

Exclusion Criteria:

1. History of other malignancy, unless disease free for at least 3 years. At thediscretion of the Principal Investigator, subjects in remission for 1-2 years priorto enrollment may be deemed eligible after considering the nature of othermalignancy, likelihood of recurrence during one year following CAR therapy, andimpact of prior treatment on risk of CD19/CD22-CAR T cells. Subjects in remission <1year 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.

2. Presence of fungal, bacterial, viral, or other infection that is uncontrolled.Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding toactive treatment.

3. Known history of infection with any of the following:

• HIV

• Hepatitis B (HBsAg positive)

• Hepatitis C virus (anti-HCV positive) A history of hepatitis B or hepatitis Cis permitted if the viral load is undetectable per quantitative PCR and/ornucleic acid testing.

4. Presence of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,cerebellar disease, or any autoimmune disease with CNS involvement that in thejudgment of the investigator may impair the ability to evaluate neurotoxicity.

5. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina,or other clinically significant cardiac disease within 12 months of enrollment

6. Any medical condition that in the judgement of the investigator is likely tointerfere with assessment of safety or efficacy of study treatment

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

8. Women who are pregnant or breastfeeding

9. 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.

10. Previous treatment with interleukin-2 or interleukin-15.

11. Confirmed diagnosis of relapsed/refractory biphenotypic BT cell ALL

12. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoidarthritis, systemic lupus) requiring systemic immunosuppression/systemic diseasemodifying agents within the last 2 years