Please select the eligibility criteria that correspond to the clinical trial below.
Title: Sequential Infusion of Anti-CD19 and Anti-CD20 Chimeric Antigen Receptor(CAR) T Cells Against Relapsed and Refractory B-cell Lymphoma
Brief Summary: Cluster of differentiation antigen 19(CD19) specifically presents in B lymphocyte cell lines steadily,while not in most normal tissue,including pluripotent hematopoietic stem cells.Cluster of differentiation antigen 20(CD20) presents in 90% of B-cell lymphomas.CD19 antigen is a well-established target for B-cell lymphomas treatment as well as CD20 antigen.Both CD19-targeting CAR T Cells and CD20-targeting CAR T Cells can be used as adoptive cellular immunotherapies for B-cell lymphomas.Though two kinds of single target treatments were proved can induce recession of B-cell lymphomas, the risk of cancer cells to escape and tumor recurrence are still existed. There are no report about combination transfer of two kinds of single target treatments.This research aimed emphasis on safety and therapeutic efficacy evaluation,as well as if combination transfer can decrease recurrence rate.


Options:
A: Inclusion Criteria:

* signed written informed consent obtained prior to study procedures
* histologically-confirmed relapsed or refractory CD20+ B-cell lymphoma of one of the following types, with documented disease progression or recurrence following the immediate prior therapy: DLBCL (regardless of cell of origin or underlying molecular genetics), MCL, PMBCL, Gr3b-FL, TH-FL (prior dx of FL before transforming to DLBCL).
* biopsy-confirmed CD20+ expression of the underlying malignancy with disease progression following immediate prior therapy
* at least 1 measurable lesion on imaging.
* must have received adequate prior therapy for the underlying CD20+ B-cell lymphoma, defined as an anti-CD20 mAb in combination with an anthracycline-containing chemotherapy regimen (i.e. chemo-immunotherapy) and at least one of the following:

  * biopsy-proven refractory disease after frontline chemo-immunotherapy
  * relapse within 1 year from frontline chemo-immunotherapy and ineligible for autologous hematopoietic stem cell transplant (auto-HSCT)
  * for subjects with DLBCL, PMBCL, and Gr3b-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT
  * for subjects with TH-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT. At least 1 prior regimen with an anti-CD20 mAb in combination with chemotherapy is required following documented transformation
  * for subjects with MCL (confirmed with cyclin D1 expression or evidence of t(11;14) by cytogenetics, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR): relapsed or refractory disease after at least 1 prior regimen with chemo-immunotherapy (prior auto-HSCT is allowable)
* ECOG 0 or 1
* life expectancy of at least 6 months
* platelet count greater than 50,000/µL

Exclusion Criteria:

* known active central nervous system (CNS) involvement by malignancy.
* prior treatment as follows:

  * alemtuzumab within 6 months of enrollment
  * fludarabine, cladribine, or clofarabine within 3 months of enrollment
  * external beam radiation within 2 weeks of enrollment
  * mAb (including rituximab) within 2 weeks of enrollment
  * other lymphotoxic chemotherapy (including steroids except as below) within 2 weeks of enrollment
  * experimental agents within 3 half-lives prior to enrollment, unless progression is documented on therapy
* clinically significant cardiac disease
* clinically significant active infection
* clinically significant CNS disorder
* clinical history, prior diagnosis, or overt evidence of autoimmune disease
* known bone marrow involvement due to underlying malignant disease, in dose-escalation phase only
B: Inclusion Criteria:

1. The subject or her/his legally guardian(s) must sign the informed consent form approved by the Institutional Ethics Committee (IEC) prior to any screening procedures;
2. Subjects aged 18 years or older with relapsed or refractory DLBCL (including primary mediastinal large B-cell lymphoma and transformed follicular lymphoma), of which refractory is defined as:

   * Have no response to the recent treatment including:

     * The best response to the treatment regimen is progressive disease (PD) ,or;
     * stable disease(SD) which maintained less than 6 months after the last treatment, or;
   * not suitable for autologous hematopoietic stem cell transplantation (ASCT), or ASCT refractory, including:

     * progressive disease after ASCT or relapse within 12 months (relapse must be confirmed by biopsy), or;
     * If remedial treatment is given after ASCT, the subject must have no response or relapse after the last treatment.
3. Subjects who have previously received ≥2 lines treatment, and at least including:

   * Anti-CD20 monoclonal antibody(rituximab), unless the CD20 negative;
   * A chemotherapy regimen containing anthracyclines;
   * The DLBCL patients who transformed from follicular lymphoma must have previously received chemotherapy for follicular lymphoma and have developed chemotherapy-refractory diseases after transform to DLBCL.
4. Confirmation for either CD19 or CD20 positivity using immunohistochemistry or flow cytometry(accepting the previous results from the a third-level grade A hospitals before the collection of peripheral blood mononuclear cells or peripheral blood. For CD20 positive only, the investigator needs to determine whether the treatment benefit);
5. According to the preliminary assessment of Hodgkin's lymphoma and non-Hodgkin's lymphoma, staging and response assessment recommendations (2014 version), there is at least one measurable lesion at baseline;
6. If the subject has received a single target in the past, such as CD19-CAR cell therapy, it must be confirmed that the disease has progressed or relapsed after treatment and is at least 1 month from the planned single collection period
7. Life expectancy ≥12 weeks;
8. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening;
9. Adequate organ function:

   * Renal function defined as:

     * A serum creatinine of ≤1.5 × Upper Limit of Normal(ULN), or;
     * Estimated Glomerular Filtration Rate (eGFR) ≥60 ml/min/1.73m2；\[eGFR=186×（age）-0.203×SCr-1.154（mg/dl）， female ×0.742 on the basis of the calculation results\]；
   * Liver function defined as:

     * Alanine aminotransferase (ALT)≤ 5 × Upper Limit of Normal(ULN) for age, and;
     * Total bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN.
   * Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and blood oxygen saturation \> 91% on room air;
10. Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA);
11. Adequate bone marrow reserve without transfusions defined as:

    * Absolute neutrophil count (ANC) \>1×10\^9 /L；
    * Absolute lymphocyte count (ALC) ≥0.3×10\^9 /L；
    * Platelets ≥50×10\^9 /L;
    * Hemoglobin \> 8.0 g/dl;
12. Subjects who use the following drugs should meet the following criteria:

    * Steroids: Therapeutic doses of steroids must be stopped 2 weeks prior to A-02 infusion. However, the following physiological replacement doses of steroids are allowed: \< 6 - 12 mg/m2/day hydrocortisone or equivalent;
    * Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks prior to sign the informed consent form;
    * Anti-proliferative therapy other than pretreatment chemotherapy within 2 weeks of A-02 infusion;
    * CD20 antibody-related treatment must be discontinued within 4 weeks of A-02 infusion or 5 half-lives (whichever is longer);
    * CNS disease prophylaxis must be stopped \> 1 week prior to A-02 infusion (e.g. intrathecal methotrexate);
13. The investigator judged that the subject recovered from the toxicity of the previous anti-tumor treatment to grade 1 or below (except for special grade 2 or below toxicity that cannot be recovered in a short period of time, such as hair loss), suitable for pretreatment. Chemotherapy and treatment of CAR-T cells;
14. Women of child-bearing potential and all male subjects must agree to use highly effective methods of contraception for at least 12 months following A-02 infusion and until CAR-T cells are no longer present by Polymerase chain reaction(PCR) on two consecutive tests.

Exclusion Criteria:

Subjects who meet any of the following criteria will not be enrolled:

1. Subjects who have received any CD19/CD20 dual-target cell therapy products before signing the informed consent form;
2. Subjects with detectable cerebrospinal fluid malignant cells or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma;
3. Subjects with current or previous history of central nervous system disease, such as seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the central nervous system;
4. Subjects who have previously received allogeneic hematopoietic stem cell transplantation (HSCT); or suitable and consenting to Autologous hematopoietic stem cell transplantation (ASCT);
5. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of A-02 infusion;
6. Investigational medicinal product within the last 30 days prior to sign the informed consent form;
7. Subjects with active hepatitis B（defined as hepatitis B surface antigen positive, or hepatitis B core antibody positive with hepatitis B virus DNA detection value \> 1000 copies/ml）or hepatitis C(HCV RNA positive);
8. Subjects positive for HIV antibody or treponema pallidum antibody;
9. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to A-02 infusion);
10. Unstable angina and/or myocardial infarction within 6 months prior to sign the informed consent form;
11. Previous or concurrent malignancy with the following exceptions:

    * Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to sign the informed consent form);
    * In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to sign the informed consent form;
    * A primary malignancy which has been completely resected and in complete remission for ≥ 5 years;
12. Pregnant or nursing women (women of childbearing age were tested positive for pregnancy during screening period);
13. Subjects with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis);
14. Other conditions that the investigator thinks he/she should not be included in this clinical trial, such as poor compliance.
C: Inclusion Criteria:

* Subjects with documented CD19-positive malignant B cell leukemia and lymphoma.

  1. Patients aged between 18 \~ 65 with malignant B cell leukemia and lymphoma.
  2. CD19-positive B cell leukemia or lymphoma.
  3. Expected survival \> 12 weeks.
  4. ECOG scores 0-1, or KPS scores \> 80.
  5. Adequate venous access for apheresis or venous sampling, and no other contraindications for leukapheresis.
  6. WBC ≥ 2.5×109/L; LY ≥ 0.7×109/L; LY% ≥ 15%.
  7. Creatinine ≤ 2.0 mg/dL (176.8 μmol/L).
  8. ALT/AST ≤ 2.5 ULN.
  9. Bilirubin ≤ 2.0 mg/dL (34.2 μmol/L).
  10. Prothrombin Time (PT) : International Normalized Ratio (INR) \< 1.7, or PT is at most 4 s longer than normal value.

All tests results should comply with the above criteria. No continuing supportive care is received.

Exclusion Criteria:

* 1. CD19-negative B cell leukemia or lymphoma. 2. Feasibility assessment during screening demonstrates \< 5% transduction of target lymphocytes, or insufficient expansion (\< 5-fold) in response to αCD3/CD28 costimulation.

  3. Pregnant or lactating women. (The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion.) 4. Active hepatitis B or hepatitis C infection. 5. HIV/AIDS infection. 6. Uncontrolled active infection. 7. Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary.

  8. Previously treatment with any gene therapy products. 9. Allergy to immunotherapy and associated drugs. 10. Patients with heart disease that is in need of treatment or with poorly controlled hypertension determined by investigators.

  11. Patients with unstable or active ulceration or with gastrointestinal bleeding.

  12. Patients with previous or planed organ transplantation. 13. Hyponatremia with concentration of sodium in the blood \< 125 mmol/L. 14. Serum potassium (baseline) \< 3.5 mmol/L (Patients can take potassium supplements to recover serum potassium level prior to participating the study).

  15. Patients need anticoagulant (e.g. Warfarin or heparin). 16. Patients need long-term antiplatelet agent (Aspirin, dose \> 300 mg/d; Clopidogrel, dose \> 75 mg/d).

  17. Any radiotherapy conducted within 4 weeks prior to blood sampling.
D: Inclusion Criteria:

* 18 Years to 70 Years, Male and female
* Survival time\>12 weeks
* B cell lymphomas diagnosed by Physical examination,pathological examination,Laboratory tests and imaging tests
* Chemotherapy failure or recurrent B cell lymphomas
* Creatinine\< 2.5mg/dl
* Glutamic-pyruvic transaminase, glutamic oxalacetic transaminase\< 3 fold of normal level
* Bilirubin\<2.0mg/dl
* Karnofsky Performance Status\>50% at the time of screening
* Adequate pulmonary, renal, hepatic, and cardiac function
* Fail in autologous or allogenic haemopoietic stem cell transplantation
* Free of leukocytes removal contraindications
* Voluntarily join CAR-T clinical trial
* Understand and sign written informed consent

Exclusion Criteria:

* Pregnant or nursing women or women with pregnancy plan in half a year
* Any infectious disease (HIV, active tuberculosis, ect.)
* Active hepatitis B, active hepatitis C infection
* Feasibility assessment proves that the efficiency of transduction of lymphocyte is below 10% or the lymphocyte amplification is below 5 fold with the costimulation of cluster of differentiation 3(CD 3)and cluster of differentiation 8(CD 8)
* Abnormal vital signs or cannot cooperate with the inspectors
* mental or psychological disease cannot cooperate with treatment and curative effect evaluation
* Highly allergic constitution or history of severe allergies, especially allergy to interleukin-2(IL-2)
* General infection or local severe infection, or other infection that is not controlled
* Dysfunction in lung, heart, kidney and brain
* Severe autoimmune diseases
* Other symptoms that are not applicable for CAR-T

Answer: D