Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase I Clinical Trial of Human CD19 Targeted T Cells Injection for Subjects With Relapsed and Refractory CD19-positive Diffuse Large B-cell Lymphoma and Follicular Lymphoma
Brief Summary: To evaluate the safety and tolerance of human CD19 targeted T Cells injection for the treatment of relapsed and refractory CD19-positive diffuse large B-cell lymphoma and follicular lymphoma. Patients will be given a conditioning chemotherapy regimen of fludarabine and cyclophosphamide followed by a single infusion of CD19 CAR+ T cells.


Options:
A: 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.
B: Inclusion Criteria:

Male or female subjects with CD19+ B cell lymphomas who have a limited prognosis (several months to \<2 year survival) with currently available therapies will be enrolled.

1. 18 to 70 Years Old, Male and female;
2. Expected survival \> 12 weeks;
3. Clinical performance status of ECOG score 0-1;
4. Pathology demonstrated that CD19-positive B-cell non-Hodgkin's lymphoma and who meet one of the following conditions:

   1. Relapsed and refractory CD19-positive Diffuse large B-cell lymphoma and Follicular lymphoma: patients previously received at least first-line and second- line treatment and fail to achieve CR;
   2. Disease recurrence after stem cell transplantation, and at least 1 years after stem cell transplantation.
5. It can establish the venous access required for collection, satisfying hemoglobin ≥ 70 g / L, neutrophils ≥ 1.0 × 10 \^ 9 / L, platelets ≥ 50 × 10 \^ 9 / L. Mononuclear cell collection can be determined by the investigators;
6. At least 1 measurable tumor foci according to the 2014 Lugano treatment response criteria;
7. Liver, kidney and cardiopulmonary functions meet the following requirements:

   1. Serum creatinine ≤ 1.5 × ULN;
   2. Left ventricular ejection fraction \>50%, no pericardial effusion and no pleural effusion (ECHO examination);
   3. Baseline oxygen saturation \> 92%;
   4. Total bilirubin ≤ 1.5 × ULN;
   5. ALT and AST ≤ 3 × ULN.
8. Able to understand and sign the Informed Consent Document.

Exclusion Criteria:

1. In the first 5 years before screening, there are malignant tumors other than diffuse large B-cell lymphoma and follicular lymphoma, except for fully treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, local prostate cancer after radical surgery，and catheter carcinoma in situ after radical surgery;
2. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood HBV DNA titer higher than the upper limit of detection; hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive; human immunodeficiency Viral (HIV) antibody positive; Positive syphilis test;
3. Any unstable systemic disease including, but not limited to, active infection (except for local infection), unstable angina pectoris, cerebrovascular accident or transient cerebral ischemia (within 6 months prior to screening), myocardial infarction (within 6 months prior to screening), congestive heart failure (New York Heart Association \[NYHA\] classification ≥ III), severe arrhythmia , liver, kidney or metabolic disease requiring medication;
4. Any other diseases could affect the outcome of this trial;
5. Any affairs could affect the safety of the subjects or outcome of this trial;
6. Pregnant or lactating women, or planned pregnancy during treatment or within 1 year after treatment, or a male subject whose partner plans pregnancy within 1 year of their cell transfusion;
7. Active or uncontrollable infection requiring systemic therapy within 14 days prior to enrollment;
8. Subjects who are receiving systemic steroid treatment and requiring long-term systemic steroid treatment during the treatment as determined by the investigator before screening (except inhalation or topical use); And subjects treated with systemic steroids (except inhalation or topical use) within 72h prior to cell transfusion;
9. Received CAR-T treatment or other gene therapies before enrollment;
10. Patients with symptoms of central nervous system or brain metastasis or have received treatment for central nervous system or brain metastasis (radiotherapy, surgery or other treatment) within 3 months before enrollment;
11. Subject suffering disease affects the understanding of informed consent or comply with study protocol;
12. The investigators consider other conditions unsuitable for enrollment.
C: Key Inclusion Criteria:

* Histologically confirmed large B-cell lymphoma
* Chemotherapy-refractory disease, defined as one or more of the following:

  * No response to first-line therapy (primary refractory disease)
  * No response to second or greater lines of therapy OR
  * Refractory after autologous stem cell transplant (ASCT)
* At least 1 measureable lesion according to the Lugano Classification (Cheson 2014).
* Individuals must have received adequate prior therapy, including at a minimum:

  * Anti-CD20 monoclonal antibody
  * An anthracycline-containing chemotherapy regimen
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate renal, hepatic, pulmonary, and cardiac function

Key Exclusion Criteria:

* Known CD19 negative or CD20 negative tumor
* History of Richter's transformation of Chronic Lymphocytic Leukemia (CLL)
* Prior CAR therapy or other genetically modified T-cell therapy
* Prior organ transplantation including prior allogeneic stem cell transplant (SCT)
* Prior CD19 targeted therapy
* Clinically significant infection or cardiopulmonary disease
* Presence of any in-dwelling lines or drains (dedicated central venous access catheters allowed)
* History or presence of central nervous system (CNS) lymphoma or nonmalignant CNS disorder or cerebrospinal fluid (CSF) malignant cells or brain metastases
* History of autoimmune disease
* History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within the last 6 months

Note: Other protocol defined Inclusion/Exclusion criteria may apply.
D: Inclusion Criteria:

* Histologically confirmed pediatric mature B-cell non-Hodgkin lymphoma (B-cell NHL) including the following subtypes; Burkitt lymphoma/ Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), and follicular lymphoma (FL) Note: Patients with B-cell NHL associated with Nijmegen breakage syndrome will be allowed.
* Patients \<25 years of age and weighing at least 6 kg at the time of screening
* Patients who have relapsed after one or more prior therapies (can include allogeneic and autologous hematopoietic stem cell transplant) or are primary refractory (have not achieved a CR or PR after the first line of therapy)
* Measurable disease by radiological criteria in all patients at the time of screening. Patients with Burkitt leukemia who don't meet radiological criteria must have bone marrow involvement of \>25% by local assessment of bone marrow aspirate and/or biopsy.
* Karnofsky (age ≥16 years) or Lansky (age \<16 years) performance status ≥60.
* Adequate bone marrow reserve without transfusions (transfusion \>2 weeks prior to laboratory assessment is allowed) defined as:

  1. Absolute neutrophil count (ANC) \>1000/mm3
  2. Platelets ≥50000//mm3
  3. Hemoglobin ≥8.0 g/dl
* Adequate organ function defined as:

  1. a serum creatinine (sCR) based on gender/age as follows: Maximum Serum Creatinine (mg/dL) Age Male Female

     1 to \<2 years 0.6 0.6 2 to \<6 years 0.8 0.8 6 to \<10 years 1.0 1.0 10 to \<13 years 1.2 1.2 13 to \<16 years 1.5 1.4

     ≥16 years 1.7 1.4
  2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN) for age
  3. Total bilirubin \<2 mg/dL (for Gilbert's Syndrome patients total bilirubin \<4 mg/dL)
  4. Adequate pulmonary function

  i. Oxygen saturation of \>91% on room air ii. No or mild dyspnea (≤Grade 1)
* Must have a leukapheresis material of non-mobilized cells accepted for manufacturing.

Exclusion Criteria:

* Prior gene therapy or engineered T cell therapy.
* Prior treatment with any anti-CD19 therapy.
* Allogeneic hematopoietic stem cell transplant (HSCT) \<3 months prior to screening and ≤4 months prior to infusion.
* Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in patients who received prior allogeneic HSCT.
* Prior diagnosis of malignancy other than study indication, and not disease free for 5 years.
* Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
* Presence of active hepatitis B or C as indicated by serology.
* Human Immunodeficiency Virus (HIV) positive test.
* Active neurological autoimmune or inflammatory disorders not related to B cell NHL (eg: Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
* Active central nervous system (CNS) involvement by malignancy.
* Patients with B-cell NHL in the context of post-transplant lymphoproliferative disorders (PTLD) associated lymphomas.

Answer: B