Please select the eligibility criteria that correspond to the clinical trial below.
Title: CD19-targeting 3rd Generation CAR T Cells for Refractory B Cell Malignancy - a Phase I/IIa Trial.
Brief Summary: Chimeric antigen receptor (CAR) T cells targeting CD19 will be evaluated for safety and efficacy in patients with B cell lymphoma or leukemia. The CAR consists of a CD19 targeting antibody scFv with three intracellular signaling domains derived from CD3 zeta, CD28 and 4-1BB. Autologous T cells will be gene engineered with the CAR gene using a retrovirus vector. Prior to T cell infusion, the patients will be subjected to preconditioning treatment. After T cell infusion, the patients will be evaluated for 24 months for adverse reactions, persistence of CAR T cells and efficacy.


Options:
A: For B acute lymphoblastic leukemia (ALL)

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

   * Chemotherapy refractory disease in subjects with B-ALL, defined as progression or stable disease after one line of therapy.
   * Recurrence of disease after achieving CR.
2. Subjects with persistent or relapsed minimal residual disease (MRD) (by flow cytometry, PCR, FISH, or next generation sequencing) require verification of MRD positivity 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 two occasions 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 T cells), then 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.
6. Subjects who have undergone autologous 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 elelino evidence of GVHD and have been without immunosuppressive agents for at least 30 days.
7. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy must be at least 30 days post CAR infusion and may not have eficence of persistnce of CAR T cells in blood smples (circulating levels of genetically modified cels of \>/= 5% by flow cytometry.
8. 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.
9. 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:
   1. There is no time restriction with regard to prior intrathecal chemotherapy (incl. steroids) provided there is complete recovery from any acute toxic effects;
   2. 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.
   3. 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;
   4. 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.
10. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia)
11. Age 18 or older
12. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or Karnofsky ≥ 60%
13. Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)

    1. ANC ≥ 1000/uL\*
    2. Platelet count ≥ 50,000/uL\*
    3. Absolute lymphocyte count ≥ 300/uL\*
    4. Adequate renal, hepatic, pulmonary and cardiac function defined as:
    5. Creatinine ≤ 2 mg/dL or creatinine clearance ≥ 60 mL/min
    6. Serum ALT or AST ≤ 5x ULN (Elevated ALT/AST associated with leukemia or lymphoma involvement of the liver will not disqualify a subject; only one value required for eligibility).
    7. Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
    8. Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an ECHO, MUGA or Cardiac MRI \[performed within 180 days or after most recent anthracycline based treatment or mediastinal radiation therapy (whichever is most recent)\]
    9. No clinically significant ECG findings
    10. No clinically significant pleural effusion
    11. Baseline oxygen saturation \> 92% on room air \* A subject will not be excluded because of cytopenia if it is felt by the investigator to be due to underlying leukemia/lymphoma.
14. 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.
15. 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)
16. 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 or 1 month after the last dose of NKTR_255, whichever is later.
17. Ability to give informed consent. Must be able to give informed consent. Subjects unable 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 preceding NKTR-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 preceding NKTR-255 infusion
* ANC ≥ 1000/µL
* No intervention with tocilizumab and/or dexamethasone within 48 hours preceding NKTR-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 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.
2. Presence of fungal, bacterial, viral, or other infection that is uncontrolled. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active 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 C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
4. 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.
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 to interfere with assessment of safety or efficacy of study treatment
7. History of severe immediate hypersensitivity reaction to any of the agents used in this study
8. Women who are pregnant or breastfeeding
9. 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.
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, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
B: Inclusion Criteria:

* Relapsed or refractory CD19+ B-cell lymphoma or leukemia.
* Measurable disease.
* Performance status ECOG 0-2.
* \>18 years old.
* Fertile females/males must consent to use contraceptives during participation of the trial.
* Signed informed consent.

Exclusion Criteria:

* Any significant medical or psychiatric illness that would prevent the patient from giving informed consent or from following the study procedures.
* Patients with primary CNS lymphoma.
* Known human immunodeficiency virus (HIV) infection.
* Active and/or severe infection (e.g. tuberculosis, sepsis and opportunistic infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection).
* Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the patient.
* Treatment with an investigational product within 30 days prior to enrollment, or at least 5 half lives of that drug, which is longest.
* Patients that do not consent to that tissue and blood samples are stored in a biobank.
* Pregnancy
C: Inclusion Criteria:

1. CD19-expressing and CD20-expressing Diffuse Large B Cell Lymphoma(DLBCL) must be assured and must be relapsed or refractory disease after at least one standard chemotherapy and one salvage regimen. According to current traditional therapies, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have disease activity that prohibits SCT at this time.
2. Patients enrolled must have an evaluated score above 60 with KPS.
3. Expected survival time of patients enrolled is over 3 months.
4. Gender is not limited, age from 14 years to 75 years.
5. Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
6. Patients are expected to survive for more than 3 months by their physicians at the time of enrollment.
7. Adequate absolute CD3 count estimated need to be assured for obtaining target cell dose based on dosage cohorts.
8. 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 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 CNS3 with marrow disease who has failed salvage systemic and intensive IT chemotherapy (and therefore not eligible for radiation)
9. Patients with isolated CNS relapse will be eligible if they have previously been treated with cranial radiation (at least 1800 cGy).
10. Ability to give informed consent.
11. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.
12. Cardiac function: Left ventricular ejection fraction greater than or equal to 40% by MUGA or cardiac MRI, or fractional shortening greater than or equal to 28% by ECHO or left ventricular ejection fraction greater than or equal to 50% by ECHO.
13. Renal function: Creatinine level of peripheral blood is required no greater than 133umol/L.
14. Patients with history of allogeneic stem cell transplantation are eligible if there is no evidence of active GVHD and no longer taking immunosuppressive agents for at least 30 days prior to enrollment.
15. Patients volunteer to participate in the research

Exclusion Criteria:

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

1. Patients are evaluated below 50 scores with KPS.
2. Evident signs suggesting that patients are potentially allergic to cytokines.
3. Frequent infection history and recent infection is uncontrolled.
4. Patients with concomitant genetic syndrome: patients with Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome
5. Active acute or chronic graft-versus-host disease (GVHD) or requirement of immunosuppressant medications for GVHD within 4 weeks of enrollment.
6. Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary. For additional details regarding use of steroid and immunosuppressant medications.
7. Pregnancy and nursing females. HIV infection.
8. Active hepatitis B or active hepatitis C.
9. Participation in a prior investigational study within 4 weeks prior to enrollment or longer if required by local regulation. Participation in non-therapeutic research studies is allowed.
10. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
11. Patients with a known history or prior diagnosis of other serious immunologic, malignant or inflammatory disease.
12. Other situations we think not eligible for participation in the research.
D: Inclusion Criteria:

* Patients with relapsed / refractory previously treated B cell malignancies (according to the World Health Organization classification; 2017)
* Patients must have received adequate prior therapy including at least two lines of prior therapies including anthracycline or bendamustine-containing chemotherapy, anti-CD20 (cluster of differentiation antigen 20) therapies and/or Brutton's tyrosine kinase (BTK) inhibitors
* Patients treated with prior CD19 targeted molecules (e.g., Blincyto) must have confirmed CD19+ disease
* Patients must be ineligible for allogeneic stem cell transplant (SCT)
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
* Estimated life expectancy of ≥ 12 weeks from the first day of SWI019 dose administered
* Willing to undergo pre- and post-treatment core needle biopsy
* Adequate hematological, renal, pulmonary, cardiac, and liver function
* Resolved adverse events of any prior therapy to either baseline or CTCAE Grade ≤1
* Women of childbearing potential, a negative pregnancy test and must agree to practice effective birth control
* Men sexually active with female partners of child bearing potential must agree to practice effective contraception
* Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other procedures

Exclusion Criteria:

* Patients diagnosed with certain disease histologies including pediatric lymphomas/leukemias, monoclonal gammopathy of undetermined significance (MGUS), T-cell histiocyte large B cell lymphoma
* Pregnant or lactating women
* Active bacterial, viral, and fungal infections
* History of allogeneic stem cell transplantation
* Treatment with any prior lentiviral or retroviral based CAR-T
* Patients receiving live (attenuated) vaccines within 4 weeks of screening visit or need for live vaccine on study
* Patients with known active central nervous system (CNS) disease. Patients with prior CNS disease that has been effectively treated may be eligible
* History of Class III or IV New York Heart Association (NYHA) heart failure, myocardial infarction, unstable angina or other significant cardiac disease within 6 months of screening
* Involvement of cardiac tissue by lymphoma
* Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP)
* HIV-1 and HIV-2 antibody positive patients

Answer: B