Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1, Open-Label Study of JWCAR029, CD19-targeted Chimeric Antigen Receptor (CAR) T Cells, for Adult Subjects With Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL)
Brief Summary: This is a single arm, open-label, dose escalation clinical study to evaluate the safety and efficacy of infusion of autologous CD19-targeted chimeric antigen receptor (CD19 CAR) T cells in adult subjects with relapsed and refractory B-cell Non-Hodgkin lymphoma.


Options:
A: Inclusion Criteria:

1. Confirmed by pathological biopsy in patients with diffuse large B cell lymphoma by standard solution treatment is invalid or recurrence of refractory, and by flow cytometry or pathological immunohistochemical examination, confirmed the tumor cell surface expression positive intervention molecular targets, mainly for the CD19 (+) and/or CD20 (+).
2. Age 3 to 75 years old, both male and female;
3. Is expected to survive more than 3 months;
4. Physical condition is good: 0-2 score ECOG score;
5. In group of four weeks before Canon imaging examination evaluation body tumor load, recommend line PET - CT examination.
6. General requirements peripheral blood as basic, normal blood T lymphocytes in peripheral blood count must \>= 0.2 x10\^9 / L;
7. No obvious abnormal heart, liver, kidney, no large wounds that haven't healed on the body;
8. Into groups to participate in voluntarily, good adherence, can cooperate test observation, childbearing age women must be 7 days before starting treatment expert pregnancy test and the results were negative, and signed a written informed consent form.

Exclusion Criteria:

1. The recurrent or refractory patients with diffuse large B cell lymphoma.
2. Organ failure, such as heart: Class III and IV; liver: to Child grading of liver function grade C; kidney: kidney failure and uremia stage; lung: symptoms of severe respiratory failure; brain: disorder of consciousness;
3. Existing serious acute infection, uncontrollable, or have fester sex and chronic infection, wound in delay no more;
4. Patients with significant graft versus host disease (GVHD) after organ transplant history or allogeneic hematopoietic stem cell transplantation;
5. Systemic autoimmune diseases or immunodeficiency disease, patients with allergic constitution;
6. Coagulation abnormalities and severe thrombosis;
7. Pregnancy and lactation women;
8. Any other chronic disease patients who have been treated with immune agents or hormone therapy;
9. Patients who have participated in other clinical trials or other clinical trials in the past 30 days;
10. The Investigator believe the patients should not participate in this experiment.
B: 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
* Biopsy-confirmed CD20+ expression of the underlying malignancy by immunohistochemical staining or flow cytometry between the most recent dose of an anti-CD20 monoclonal antibody (mAb) and study enrollment
* At least 1 measurable lesion on imaging. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
* 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 PCR): relapsed or refractory disease after at least 1 prior regimen with chemo-immunotherapy (prior auto-HSCT is allowable)
* Karnofsky performance scale ≥ 60%
* Life expectancy of at least 6 months
* ANC \> 1000/µL
* Platelet count \> 50,000/µL
* For women of childbearing potential (defined as physiologically capable of becoming pregnant), agreement to use of highly effective contraception for at least 1 year following ACTR087 infusion. For men with partners of childbearing potential, agreement to use effective barrier contraception for at least 1 year following ACTR087 infusion

Exclusion Criteria:

* Known active central nervous system (CNS) involvement by malignancy. Subjects with prior CNS involvement with their lymphoma must have completed effective treatment of their CNS disease at least 3 months prior to enrollment with no evidence of disease clinically and at least stable findings on relevant CNS imaging
* 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
* Serum creatinine ≥ 1.5 X age-adjusted upper limits of normal (ULN)
* Pulse oximetry \< 92% on room air
* Direct bilirubin ≥ 3.0 mg/dL (50 mmol/L)
* Alanine transaminase (ALT) ≥ 3 times the ULN, unless determined to be directly due to lymphoma.
* Aspartate transaminase (AST) ≥ 3 times the ULN, unless determined to be directly due to lymphoma
* Class III or IV heart failure as defined by the New York Heart Association (NYHA), history of cardiac angioplasty or stenting, documented myocardial infarction or unstable angina within 6 months prior to enrollment, cardiac ejection fraction of \< 45%, or other clinically significant cardiac disease
* Clinical history of, prior diagnosis of, or overt evidence of autoimmune disease, regardless of severity
* Clinically significant active infection, in the judgment of the investigator
* Pregnancy (negative serum pregnancy test to be obtained within 6 days prior to enrollment for subjects of childbearing potential)
* Breastfeeding
* Primary immunodeficiency
* Seropositive for Human Immunodeficiency Virus (HIV) 1 or HIV 2, or positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody
* Will need or has needed active treatment of a second malignancy within the prior 3 years before enrollment, other than FL, non-melanoma skin cancers, localized prostate cancer treated with curative intent, or cervical carcinoma in situ
* Is unable to receive any of the agents used in this study due a history of severe immediate hypersensitivity reaction (e.g. hypersensitivity to dimethyl sulfoxide (DMSO))
* History of prior allogeneic HSCT
* History of Richter's transformation from CLL
* Prior infusion of a genetically modified therapy
C: Inclusion Criteria:

* Subjects must meet all of the following criteria to be enrolled in this study:

  1. Age ≥ 18 years at the time of consent
  2. Signed written informed consent obtained prior to any study procedures
  3. Relapsed or refractory B-cell NHL.
  4. PET-positive disease BY Lugano classification
  5. Archived tumor biopsy tissue available from the last relapse and corresponding pathology report available or, if at least one tumor-involved site is deemed accessible at time of screening, willing to undergo pre-treatment biopsy (excisional when possible) for disease confirmation. If a subject has never had a complete response, a sample from the most recent biopsy is acceptable.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  7. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function
  8. Adequate vascular access for leukapheresis procedure
  9. Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy
  10. Subjects must agree to use appropriate contraception.

Exclusion Criteria:

* Subjects who meet any of the following criteria will be excluded from participation in this study:

  1. Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study)
  2. History of another primary malignancy that has not been in remission for at least 2 years.
  3. Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis
  4. Active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at the time of screening
  5. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or JWCAR029 administration
  6. Presence of acute or chronic graft-versus-host disease (GVHD)
  7. History of cardiovascular disease
  8. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
  9. Pregnant or nursing women.
  10. Prior CAR T-cell or other genetically-modified T-cell therapy, with the exception of prior JWCAR029 treatment in this protocol for subjects receiving retreatment
D: Inclusion Criteria:

1. Male or female, aged ≥18 years.
2. Willing and able to give written, informed consent.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.
4. Histologically confirmed DLBCL and large B cell lymphoma (at last relapse) subsets, including:

   Phase I and Phase II Cohort 1:
   1. DLBCL, not otherwise specified (NOS), per World Health Organisation classification and DLBCL with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit).
   2. Transformed DLBCL from FL.
   3. High-grade B cell lymphoma with MYC expression (excluding Burkitt's lymphoma)

      Phase I and Phase II Cohort 2:
   4. Transformed DLBCL from other indolent lymphomas (excluding Richter's transformation).
   5. Primary mediastinal large B cell lymphoma.
5. Chemotherapy-refractory disease, defined as one or more of the following:

   1. Stable disease (≤12 months) or progressive disease as best response to most recent chemotherapy containing regimen. Refractory disease after frontline chemo-immunotherapy is allowed.
   2. Disease progression or recurrence in ≤12 months of prior autologous haematopoietic stem cells transplantation (ASCT).

   OR
6. Relapse after ≥two lines of therapy or after ASCT. At a minimum:

   1. Patients must have received rituximab or another anti-CD20 monoclonal antibody (unless Investigator determines that tumour is CD20-negative) and an anthracycline-containing chemotherapy regimen.
   2. Patients must have either failed ASCT, or be ineligible for or not consenting to ASCT.
   3. Patients with transformed DLBCL must have received at least one line of therapy after transformation to DLBCL.
7. PET-positive disease per Lugano classification.
8. For females of childbearing potential, a negative serum or urine pregnancy test must be documented at screening, prior to pre-conditioning and confirmed before receiving the first dose of study treatment.

   For females who are not postmenopausal or surgically sterile, highly effective methods of contraception must be used during the treatment period and for at least 12 months after the last dose of study treatment.
9. For males, it must be agreed that that two acceptable methods of contraception are used.
10. Adequate renal, hepatic, pulmonary, and cardiac function defined as:

    1. Creatinine clearance ≥40 cc/min.
    2. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x ULN.
    3. Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome.
    4. LVEF ≥50% (by ECHO or MUGA) unless the institutional lower limit of normal is lower.
    5. Baseline oxygen saturation \>92% on room air and ≤Grade 1 dyspnoea.
11. Patient has adequate BM function without requiring ongoing blood product or granulocyte-colony stimulating factor support and meets the following criteria:

    1. Absolute neutrophil count ≥1.0 × 109/L.
    2. Absolute lymphocyte count ≥0.3 × 109/L (at enrolment and prior to leukapheresis).
    3. Haemoglobin ≥80 g/L.
    4. Platelets ≥75 × 109/L
12. No contra-indications for leukapheresis.

Exclusion Criteria:

1. Prior allogeneic haematopoietic stem cell transplant.
2. Females who are pregnant or lactating.
3. History or presence of clinically relevant CNS pathology such as epilepsy, paresis, aphasia, stroke within prior 3 months, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis.
4. Patients with active CNS involvement by malignancy. Patients with history of CNS involvement with malignancy may be eligible if CNS disease has been effectively treated and provided treatment was at least 4 weeks prior to enrolment (at least 8 weeks prior to AUTO3 infusion).
5. Clinically significant, uncontrolled heart disease or a recent (within 12 months) cardiac event.

   1. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded).
   2. Evidence of pericardial effusion
6. Patients with a history (within 3 months) or evidence of deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of pre-conditioning.
7. Patients with active gastrointestinal bleeding.
8. Patients with any major surgical intervention in the last 3 months.
9. Active bacterial, viral or fungal infection requiring systemic treatment. Active or latent hepatitis B infection or hepatitis C infection. Testing positive for human immunodeficiency virus, human T cell lymphotropic virus (HTLV1 and 2) or syphilis.
10. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months.
11. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the CNS.
12. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneumonia, or idiopathic pneumonitis.
13. History of other malignant neoplasms unless disease free for at least 24 months (carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal therapy allowed).
14. Prior treatment with PD1, PD-L1, or cytotoxic T lymphocyte-associated protein-4-targeted therapy, or tumour necrosis factor (TNF) receptor superfamily agonists within 6 weeks prior to AUTO3 infusion.
15. Prior treatment with investigational or approved gene therapy or cell therapy products until a dose level has treated at least three patients and has been declared safe.
16. Prior CD19 or CD22 targeted therapy.
17. The following medications are excluded:

    1. Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 72 hours prior to AUTO3 administration. However, physiological replacement, topical, and inhaled steroids are permitted.
    2. Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis or AUTO3 infusion.
    3. Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 1 week prior to leukapheresis (2 weeks for lymphodepleting chemotherapy).
    4. Antibody therapy use including anti-CD20 therapy within 2 weeks prior to AUTO3 infusion, or 5 half-lives of the respective antibody, whichever is shorter.
    5. Granulocyte-colony stimulating factor less than 10 days prior to leukapheresis.
    6. Live vaccine ≤4 weeks prior to enrolment.
    7. Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning chemotherapy.
18. Prior limited radiation therapy within 4 weeks of AUTO3 infusion or within 24 weeks for definitive radiation to chest.
19. Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
20. Known allergy to albumin, dimethyl sulphoxide (DMSO), cyclophosphamide or fludarabine, pembrolizumab or tocilizumab.
21. Any contraindications to receive anti-PD1 antibody pembrolizumab will be excluded from cohorts requiring administration of pembrolizumab.
22. Patients, who in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study.
23. Any other condition that in the Investigator's opinion would make the patient unsuitable for the clinical trial.

    Phase I outpatient cohort:
24. Subjects who do not have caregiver support (in line with institutional outpatient transplant guidelines) for outpatient/ambulatory care setting.
25. Subjects who are staying greater than 60 minutes (or whatever is permissible per institutional outpatient transplant guidelines) from the clinical trial site at the time of treatment.

For AUTO3 Infusion: Patients meeting any of the following exclusion criteria must not be treated with AUTO3 or have treatment delayed until they no longer meet these criteria:

1. Severe intercurrent infection.
2. Requirement for supplementary oxygen or active pulmonary infiltrates.
3. Clinical deterioration of organ function (renal and hepatic) exceeding the criteria set at study entry.

Answer: C