Please select the eligibility criteria that correspond to the clinical trial below.
Title: COBALT: Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation
Brief Summary: The purpose of this study is to administer novel cluster of differentiation antigen 19 (CD19) specific Chimeric Antigen Receptor T-cells (CAR19 T-cells) to patients with relapsed or resistant Diffuse Large B Cell Lymphoma (DLBCL) to assess the safety and efficacy of this strategy as a bridge to allogeneic transplantation.


Options:
A: 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.
B: Inclusion Criteria:

* Written informed consent must be obtained prior to any screening procedures
* Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment.

  .- Relapsed or refractory disease after ≥2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT
* Measurable disease at time of enrollment
* Life expectancy ≥12 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening
* Adequate organ function:

  * Renal function defined as:

    * A serum creatinine of ≤1.5 x Upper Limit of Normal ULN OR
    * Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m\^2
  * Liver function defined as:

    * Alanine Aminotransferase (ALT) ≤ 5 times the Upper Limit of Normal (ULN) for age
    * 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 x ULN and direct bilirubin ≤ 1.5 x ULN
  * Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation \> 91% on room air
  * Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA)
  * Adequate bone marrow reserve without transfusions defined as:

    * Absolute neutrophil count (ANC) \> 1.000/mm\^3
    * Absolute lymphocyte count (ALC) ≥ 300/mm\^3 and absolute number of CD3+ T cells \> 150/mm\^3
    * Platelets ≥ 50.000//mm\^3
    * Hemoglobin \> 8.0 g/dl
  * Must have an apheresis product of non-mobilized cells accepted for manufacturing
  * Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests

Exclusion Criteria:

* Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
* Treatment with any prior gene therapy product
* Active Central Nervous System (CNS) involvement by malignancy
* Prior allogeneic HSCT
* Eligible for and consenting to HSCT
* Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
* Investigational medicinal product within the last 30 days prior to screening
* The following medications are excluded:

  * Steroids: Therapeutic doses of steroids must be stopped \>72 hours prior to leukapheresis and \>72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: \< 12 mg/m\^2/day hydrocortisone or equivalent
  * Immunosuppression: Any other immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators)
  * Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion
* Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, and hydroxyurea) must be stopped \> 72 hour prior to leukapheresis and \> 72 hours prior to CTL019 infusion
* Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion
* Fludarabine may be associated with prolonged lymphopenia. This should be taken into consideration when evaluating the optimal timing for leukapheresis collection.

  * Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer
  * CNS disease prophylaxis must be stopped \> 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)
* Prior radiation therapy within 2 weeks of infusion
* Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive )
* HIV positive patients
* Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
* Unstable angina and/or myocardial infarction within 6 months prior to screening
* Previous or concurrent malignancy with the following exceptions:

  * Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
  * In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
  * A primary malignancy which has been completely resected and in complete remission for ≥ 5 years
* Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 24 hours before lymphodepletion
* Intolerance to the excipients of the CTL019 cell product
* Cardiac arrhythmia not controlled with medical management
* Prior treatment with any adoptive T cell therapy
* Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Richter's transformation, and Burkitt lymphoma
* Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)
C: 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
D: Inclusion Criteria:

1. Age 16-65 years
2. Confirmed diagnosis of CD19+ DLBCL
3. Primary resistant or relapsed disease failing to achieve metabolic Complete Response (CR) to 1st line salvage, or relapse post autograft failing to achieve metabolic CR following a single further cycle of salvage
4. Potential allogeneic transplant candidate
5. Agreement to have a pregnancy test, use adequate contraception for 12 months post-CAR19 T-cell infusion
6. Karnofsky performance status \>60
7. Written informed consent

Exclusion Criteria:

1. Women who are pregnant or lactating
2. Prior allogeneic transplantation
3. Progressive disease following most recent salvage prior to planned leucapheresis (those with mixed response are eligible)
4. Prior history of ischaemic heart disease, dysrhythmias, abnormal electrocardiogram (ECG)(Left Bundle Branch Block (LBBB)), Multiple Gated Acquisition (MUGA) left ventricular ejection fraction (LVEF) \<40%
5. Exclusions for proceeding to allogeneic transplantation (active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV); liver function test (LFT) \>3 x upper limit of normal (ULN); Creatinine Clearance (CrCl) \<40 ml/min; or other comorbidity that precludes transplantation)
6. Known central nervous system (CNS) involvement or cerebral vascular accident (CVA) within prior 3 months
7. Patients receiving corticosteroids at a dose of \> 10mg prednisolone per day (or equivalent)
8. Use of rituximab within the last 2 months prior to CAR19 T-cell infusion
9. Active autoimmune disease requiring immunosuppression
10. Life expectancy \<3 months
11. Known allergy to albumin or dimethylsulfoxide (DMSO)
12. Any contraindication to the administration and use of ifosfamide, epirubicin, etoposide, fludarabine and cyclophosphamide.

Answer: D