Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase 1/1b Study of Redirected Autologous T Cells Engineered to Contain an Anti CD19 and Anti CD20 scFv Coupled to CD3ζ and 4-1BB Signaling Domains in Patients With Relapsed and/or Refractory CD19 or CD20 Positive B Cell Malignancies
Brief Summary: This is a phase 1/1b, interventional single arm, open label, treatment study designed to evaluate the safety and feasibility of infusion of autologous T cells engineered to contain an anti-cluster of differentiation 19 (CD19) and anti-cluster of differentiation 20 (CD20) single chain variable fragment (scFv) coupled to cluster of differentiation CD3ζ (CD3ζ) and co-stimulatory domain 4-1BB (4-1BB) signaling domains in patients with relapsed and/or refractory CD19 or CD20 positive B cell malignancies


Options:
A: 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.
B: Inclusion Criteria

1. Diagnosis of B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) / small lymphocytic leukemia (SLL): Patients must be aged≥18 years with relapsed, refractory disease and no available curative options that meet clinical criteria to initiate treatment.
2. Patients with B-cell NHL or CLL/SLL must have either CD19 or CD20 positive disease on most recent biopsy performed (a repeat biopsy is not mandatory for this study except as noted below). A minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry on prior or repeat biopsy is required.
3. Absolute CD3+ T cell count ≥50/mm\^3.
4. MRI brain and Lumbar Puncture with cerebral spinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement only in patients with history of CNS involvement.
5. Measurable disease must have been documented within 4 weeks of the time of consent defined as the following by disease specific subtype:

   1. B-cell NHL: Active disease defined as nodal lesions greater than 20 mm in the long axis or extranodal lesions \>10 mm in long and short axis or bone marrow involvement that is biopsy proven.
   2. CLL/SLL: Active disease by either bone marrow, peripheral flow cytometry, or CT and/or positron emission tomography (PET) imaging with nodal disease.
6. Patients should have failed at least two lines of a standard treatment and meet disease specific criteria detailed below:

   1. CLL/SLL: measurable disease as defined above that has relapsed after at least one line of chemo-immunotherapy and progressed or intolerant to ibrutinib monotherapy.
   2. CD19 or CD20 positive B cell NHL limited to the following histologies: Advanced Stage III or IV Follicular Lymphoma, Diffuse Large B cell Lymphoma and associated subtypes (e.g. aggressive B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein Barr virus positive diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone lymphoma, and Richter's transformation) and Mantle cell lymphoma. Specific criteria include:

      * Patients must have active, measurable disease after two lines of cytotoxic chemotherapy of which one must be anthracycline containing.
      * Must have received Rituximab or another CD20 antibody and at minimum two chemotherapy regimens appropriate for their disease.
      * Either failed autologous transplant or ineligible to receive autologous transplant
7. Karnofsky performance score ≥70. See Appendix A for scales.
8. Normal Baseline Neurological Evaluation: Mini-Mental Status Exam Score 24-30.
9. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<5 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase \<5 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.
10. Adequate renal function, defined as creatinine clearance\>60 ml/min
11. Able to provide written informed consent.
12. Agree to practice birth control during the study.
13. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥35% (by echocardiogram or MUGA) and adequate pulmonary function as indicated by room air oxygen saturation of ≥92%.
14. Expected survival \>12 weeks.
15. Negative urine or serum pregnancy test in females of child bearing potential at study entry and again within 48 hours' prior lymphodepleting chemotherapy.
16. Patients with prior blinatumomab treatment require repeat biopsy post-blinatumomab treatment that demonstrates CD19 or CD20 positive disease.
17. Meet criteria for regarding fertility and contraception.
18. Central line access will be required for CAR-20/19-T cell infusion.

Exclusion Criteria

1. Positive beta-human chorionic gonadotropin in females of child-bearing potential.
2. Patients with known systemic allergy to bovine or murine products.
3. Known prior positive serology for human anti-mouse antibody (HAMA).
4. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.
5. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon: such as systemic lupus erythematous, Wegner's glomerulonephritis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (AIHA, ITP) requiring steroid therapy defined as \>20 mg of prednisone or equivalent daily.
6. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
7. Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of ≥4 weeks required from administration of any other investigational agents on other clinical trials prior to enrollment on this CAR-T protocol.
8. Refusal to participate in the long-term follow-up protocol.
9. Patients with active CNS involvement by malignancy on MRI or by lumbar puncture.

   a. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was \>4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.
10. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are \<100 days' post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
11. Previous CAR-T cell therapy directed at either CD19 or CD20 within 100 days of planned CAR-20/19-T cell infusion (does not include re-enrollment)

    a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry.
12. Anti-CD20 antibody treatment within 4 weeks of cell infusion.
13. Anti-CD19 antibody treatment within 4 weeks of cell infusion.
14. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell infusion.
15. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells.
16. Patients post solid organ transplant who develop high grade lymphomas or leukemias.
17. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.

Special Criteria for regarding Fertility and Contraception

Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure \[hysterectomy or bilateral oophorectomy\]) must have a negative serum or urine pregnancy test performed as part of eligibility criteria and again within 48 hours of initiation of lymphodepleting chemotherapy.

Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception during the follow-up period of the protocol.

Acceptable birth control includes a combination of two of the following methods:

* Condoms\* (male or female) with or without a spermicidal agent.
* Diaphragm or cervical cap with spermicide
* Intrauterine device (IUD)
* Hormonal-based contraception Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception.
C: * INCLUSION CRITERIA:

  1. Patient must have a cluster of differentiation 19 (CD19)-expressing B-cell lymphoma. Patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and diffuse large B-cell lymphoma transformed from follicular lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab.
  2. Confirmation of diagnosis of B-cell malignancy and positivity for CD19 confirmed by the Laboratory of Pathology of the National Cancer Institute (NCI). The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood, fine needle aspirates and bone marrow samples.
  3. Patients must have indications for treatment for their B-cell malignancy at the time of enrollment on this trial.
  4. Greater than or equal to 18 years of age and less than or equal to age 70.
  5. Willing to sign a durable power of attorney.
  6. Able to understand and sign the Informed Consent Document.
  7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  8. Life expectancy of greater than three months.
  9. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  10. Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  11. Serology:

      * Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.).
      * Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive. Then patients must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
  12. Hematology:

      * Absolute neutrophil count greater than or equal to 1000/mm\^3 without the support of filgrastim.
      * Platelet count greater than or equal to 50,000/mm\^3.
      * Hemoglobin greater than 8.0 g/dl.
      * Lymphocyte count less than or equal to 4,000/ mm\^3
  13. Chemistry:

      * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 5 times the upper limit of normal.
      * Serum creatinine less than or equal to 1.6 mg/dl
      * Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl
  14. More than three weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patient toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
  15. Normal cardiac ejection fraction and no evidence of pericardial effusion as determined by an echocardiogram.

EXCLUSION CRITERIA:

1. Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
2. Patients that have active hemolytic anemia.
3. Patients with active brain metastases, or with a history of any central nervous system (CNS) metastases or cerebrospinal fluid malignant cells.

   Note: patients who are asymptomatic but are found to have malignant cells in the cerebrospinal fluid (CSF) on lumbar puncture prior to treatment will be considered eligible.
4. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
5. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
7. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
8. Concurrent systemic steroid therapy.
9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
10. History of allogeneic stem cell transplantation
11. Patients with cardiac atrial or cardiac ventricular lymphoma involvement.

Screening Evaluation:

Within 4 weeks prior to starting the chemotherapy regimen:

1. Complete history and physical examination, including, weight and vital signs, noting in detail the exact size and location of any lesions that exist. (Note: patient history may be obtained within 8 weeks.)
2. Chest x-ray
3. Electrocardiography (EKG)
4. Baseline computed tomography (CT) of the chest, abdomen and pelvis, positron emission tomography (PET) scan, and brain magnetic resonance imaging (MRI) to evaluate the status of disease. Additional scans and x-rays may be performed if clinically indicated based on patient signs and symptoms.
5. HIV antibody titer and Hepatitis B surface antigen (HbsAG) determination, and anti HCV, (Note: May be performed within 3 months of the chemotherapy start date).
6. Anti cytomegalovirus (CMV) antibody titer, herpes simplex virus (HSV) serology, and Epstein-Barr virus (EBV) panel (Note: patients who are known to be positive for any of the above do not need to be retested; may be performed within 3 months of chemotherapy start date)
7. Patients with a left ventricular ejection fraction (LVEF) of less than or equal to 55% will not proceed to treatment (Note: may be performed within 8 weeks of treatment).
8. Cluster of differentiation 19 (CD19) staining of malignant cells by immunohistochemistry or flow cytometry (testing is permitted to be conducted at any time prior to this point).
9. All patients must have a T cells, B cells, and natural killer cells (TBNK) for Peripheral blood cluster of differentiation 3 (CD3) count and CD19#.
10. Patients with a history of leptomeningeal disease, or signs/symptoms suggestive of leptomeningeal involvement, or with symptoms of central nervous system malignancy such as new onset severe headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar puncture for examination of cerebral spinal fluid.
11. Patients may undergo lumbar puncture (LP) for flow cytometry of the CSF in order to assess the presence of CD19 positive lymphocytes for potential correlation with neurologic toxicity. Patients who have no neurologic symptoms at the time of LP will be eligible for enrollment regardless of the results of the flow cytometry.

    Within 14 days prior to starting the chemotherapy regimen:
12. Chem 20: (Sodium (Na), Potassium (K), Chloride (Cl), Total carbon dioxide (CO2) (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/glutamic pyruvic transaminase (GPT), AST/glutamic oxaloacetic (GOT), Total Bilirubin, Direct Bilirubin, lactate hydrogenase (LD), Total Protein, Total creatine kinase (CK), Uric Acid)
13. Thyroid panel
14. Complete blood count (CBC) with differential and platelet count
15. Prothrombin time (PT)/partial thromboplastin time (PTT)
16. Urinalysis and culture, if indicated

    Within 7 days prior to starting the chemotherapy regimen:
17. Beta-human chorionic gonadotropin (βHCG) pregnancy test (serum or urine) on all women of child-bearing potential
18. ECOG performance status of 0 or 1
D: Inclusion Criteria:

* Patient with relapsed or refractory B-cell malignancy
* Age 1-50 years
* CD19 expression shown by flow cytometry or immunohistochemistry on at least 70% of leukemic blasts / lymphoma cells
* Adequate CD3 count (above 250 CD3+ cells per microliter blood)
* Clinical performance status: Patients \> 10 years of age: Karnofsky ≥ 50%; Patients ≤ 10 years of age: Lansky scale ≥ 50%. Exception for neurologic symptoms (e.g. paralysis) that are explained by the malignancy.
* Females of child-bearing potential must have a negative pregnancy test
* Cardiac function: Left ventricular ejection fraction \>45% or shortening fraction \>28%
* For patients following allogeneic bone marrow transplantation - at least 100 days post BMT with no signs or symptoms of active graft-versus-host disease.

Key Exclusion Criteria:

* Hyperleukocytosis (WBC\>50,000) or rapidly progressive disease
* Pregnant or breast-feeding females
* Hepatic dysfunction, defined as bilirubin \> x2 upper normal limit (except when explained by hemolysis or Gilbert) or serum glutamate oxaloacetate transaminase \> x25 upper normal limit.
* Hepatitis B, Hepatitis C or HIV infection.
* Anti-neoplastic treatment given in the 2 weeks prior to apheresis, with the exception of intrathecal chemotherapy.
* Active immunosuppressive therapy

Answer: B