Please select the eligibility criteria that correspond to the clinical trial below.
Title: Autologous T Cells With a Chimeric Antigen Receptor in Patients With CD19-positive Malignant B Cell Leukemia and Lymphoma
Brief Summary: This study is designed for determining the safety and relative engraftment levels of the redirected autologous T cells transduced with the anti-CD19 lentiviral vector in patients with CD19-positive B cell leukemia and malignant lymphoma.


Options:
A: Inclusion Criteria:

1. Patients must have a diagnosis of relapsed or refractory B-cell NHL:

   * DLBCL, Mantle Cell, Follicular Lymphoma, Lymphoplasmacytic lymphoma, Small Lymphocytic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Burkitt Lymphoma, transformed lymphoma.

     * Subjects with small lymphocytic lymphoma (SLL) must have progressed after at least 2 prior therapies and prior treatment with or intolerance of both ibrutinib and venetoclax.
     * Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma and transformed lymphoma must have relapsed or failed to respond to \>= 2 prior lines of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline.
     * Subjects with indolent lymphomas ((nodal or extranodal marginal zone lymphoma, follicular lymphoma and lymphoplasmacytic lymphoma) must have relapsed after or been refractory to \>=2 prior lines of multi-agent chemoimmunotherapy including prior exposure to rituximab and at least 2 other chemotherapy agents.
     * For subjects with Mantle cell lymphoma, previous lines of therapy may include multiagent chemotherapy including alkylating agent or anthracycline and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor therapy.
   * Positron Emission Tomography (PET) -positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"
   * At least one of the following:

     * Primary refractory or early relapse (first remission \< 12 months) and not eligible for stem cell transplant
     * Relapsed or refractory disease after two or more lines of systemic therapy
   * No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.
2. CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19 positivity has to be re-established on the most recent biopsy.
3. Age \>=18 years at the time of consent
4. Absolute lymphocyte count \> 100/ (microliter)
5. Eastern Cooperative Oncology Group (ECOG) performance status \< 2
6. Adequate organ function, defined as:

   * Adequate bone marrow function for apheresis and lymphodepleting chemotherapy

     * Hemoglobin (Hgb) \>8 grams per deciliter (gm/dl) (transfusions allowed)
     * Platelets \>50,000/microliter (uL) (transfusions allowed)
     * Absolute Neutrophil Count (ANC) \> 500/uL
   * Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 3 x institutional upper limit of normal (ULN) and Total bilirubin \< 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
   * Serum Creatinine \< 2 x the institutional ULN
   * Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) \> 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) within 3 months of screening. Repeat testing may occur at Investigator's discretion.
7. Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line).
8. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-CD19 CAR-T cells
9. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method
10. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

1. Autologous transplant within 6 weeks of planned CAR-T cell infusion
2. Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol
3. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast).
4. HIV seropositivity
5. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
6. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
7. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
8. Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.
10. Body weight \<40 kilograms(kg)

Eligibility for Infusion of Investigational Product:

Subjects will undergo an evaluation of eligibility on day 1 prior to infusion of anti-CD19 CAR-T cell product. This eligibility criterion will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions:

1. No significant laboratory abnormalities. Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.
2. ECOG performance status \< 2
3. No evidence of uncontrolled intercurrent illness including, but not limited to ongoing or active infection, inflammatory response, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations.
4. No new neurologic symptoms suggestive of an active central nervous system condition, or uncontrolled CNS involvement by lymphoma.
5. No corticosteroid use within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).
B: Inclusion Criteria:

* (1) Age ≥ 18, upper limit 75, unlimited for men and women;

  (2) ECOG score 0-3;

  (3) Histologically confirmed diffuse large B-cell lymphoma (DLBCL) \[according to who 2008\];

  (4) CD19 was positive (immunohistochemistry or flow cytometry).

  (5) The definition of refractory or relapse of DLBCL is: no complete remission after 2-line treatment; disease progression in any treatment process, or disease stabilization time equal to or less than 6 months; or disease progression or relapse within 12 months after hematopoietic stem cell transplantation;

  (6) The previous treatment of diffuse large B cell lymphoma must include rituximab (CD20 mAb) and anthracycline;

  (7) There should be at least one measurable focus. It is required that any length of lymph node focus should be greater than 1.5cm or any length of extranodal focus should be greater than 1.0cm. PET-CT scan focuses should have uptake (SUV is greater than liver blood pool);

  (8) The absolute value of neutrophils in peripheral blood ≥ 1000 / μ L, platelet ≥ 45000 / μ L;

  (9) Heart, liver and kidney function: creatinine \< 1.5mg/dl; ALT (alanine aminotransferase) / AST (aspartate aminotransferase) 2.5 times lower than the normal upper limit; total bilirubin \< 1.5mg/dl; heart ejection fraction (EF) ≥ 50%;

  (10) Sufficient understanding ability and voluntary signing of informed consent;

  (11) Those with fertility must be willing to use contraceptive methods;

  (12) According to the judgment of the researchers, the expected survival time is more than 4 months;

  (13) Willing to follow visit schedule, administration plan, laboratory inspection and other test steps.

Exclusion Criteria:

* (1) History of other tumors;

  (2) Hematopoietic stem cell transplantation was performed within 6 weeks;

  (3) Any target car-t treatment was performed within 3 months before the car-t treatment;

  (4) Previous use of any commercially available PD-1 mAb;

  (5) Cytotoxic drugs, glucocorticoids and other targeted drugs were received within 2 weeks before cell collection;

  (6) Active autoimmune diseases;

  (7) Uncontrollable infection of active bacteria and fungi;

  (8) HIV infection, syphilis infection; active hepatitis B or C: hepatitis B: HBV-DNA ≥ 1000IU / ml; hepatitis C: HCV RNA positive and liver function abnormal.

  (9) Known central nervous system lymphoma.
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:

* 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.

Answer: D