Decitabine-primed Tandem CD19/CD20 CAR T Cells Plus Epigenetic Agents in Aggressive r/r B-NHL With Huge Tumor Burden

Inclusion Criteria:

1. Age ≥16 and ≤ 65 years.
2. Sum of the Product of the perpendicular Diameters for multiple lesions, SPD ≥ 100cm^2or the largest-diameter of tumor ≥ 10cm.
3. Histologically confirmed CD20+ and/or CD19+ aggressive B-cell non-Hodgkin lymphoma (NHL), including the following types defined by the World Health Organization (WHO) 2016:

• Diffuse large B-cell lymphoma (DLBCL).
• High grade B-cell lymphoma(HGBL).
• Other aggressive B-cell lymphoma.

4. Refractory disease or relapse after treatment with ≥2 lines of chemotherapy, includingrituximab and anthracycline and either having failed autologous hematopoietic stemcell transplantation (HSCT), being ineligible for autologous HSCT or not consenting toautologous HSCT. We defined chemotherapy-refractory disease as meeting one or more of the followingcriteria:

• No response to first-line therapy (primary refractory disease).
• No response to second-line or later therapy.
• Progressive disease (PD) as the best response to the most recent therapy regimen.
• Stable disease (SD) as the best response after at least 2 cycles of the mostrecent line of therapy with an SD duration of no longer than 6 months from thelast dose of therapy. Failure following autologous HSCT was defined as follows:
• PD or relapsed disease ≤12 months after autologous stem cell transplantation (ASCT) (requires biopsy-proven recurrence in relapsed subjects).
• No response or relapse after salvage therapy is given post-ASCT.

5. PD or relapse ≥3 months after treatment with targeted CD19 therapy, including CD19 CART cells or anti-CD19/anti-CD3.
6. Successful leukapheresis assessment and preculture of T cells.
7. Life expectancy > 3 months.
8. Adequate organ function:

• Creatinine < 1.6 mg/dL (140 µmol/L) or creatinine clearance ≥60 mL/min.
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3× upper limitof the normal range.
• Bilirubin <2.0 mg/dL unless the subject had Gilbert's syndrome (<3.0 mg/dL).
• A minimum level of pulmonary reserve defined as ≤ grade 1 dyspnoea and pulseoxygenation > 91% with room air.
• Cardiac ejection fraction ≥50%, no evidence of pericardial effusion as determinedby an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings.

9. An adequate bone marrow reserve defined as:

• Absolute neutrophil count (ANC)>1,000/mm3.
• Absolute lymphocyte count (ALC)≥300/mm3.
• Platelet count ≥ 50,000/mm3.
• Haemoglobin > 7.0 mg/dL.

10. Measurable or assessable disease according to the "IWG Response Criteria for MalignantLymphoma" (Cheson 2014). Patients in complete remission (CR) with no evidence ofdisease were not eligible.
11. Informed consent/assent requiring that all patients have the ability to understand andthe willingness to provide written informed consent.

Exclusion Criteria:

1. Patients with definite involvement of the gastrointestinal tract. Endoscopy should beperformed to confirm gastrointestinal involvement in suspected patients. However,patients with central nervous system (CNS) involvement were cautiously enrolled inthis clinical study.
2. Detection of a clear HAMA effect in patients with prior CD19 CAR T cell treatmentfailure or recurrence, or negative tumour puncture detection of CD19 and CD20.
3. Pregnant or lactating women.
4. Uncontrolled active bacterial or viral infection (active hepatitis B or hepatitis Cinfection, HIV infection) or treponema pallidum infection.
5. Class III/IV cardiovascular disability according to the New York Heart AssociationClassification and a cardiac ejection fraction ≥50%.
6. History of allo-HSCT.
7. Requirement for urgent therapy due to tumour mass effects such as respiratoryobstruction or blood vessel compression.
8. Current or expected need for systemic corticosteroid therapy.
9. Any organ failure.
10. Patients with a second tumour requiring therapy or intervention.
11. Eastern Cooperative Oncology Group (ECOG) performance status score between 0 and 2.
12. Subjects considered unlikely to complete all protocol-required study visits orprocedures, including follow-up visits, or comply with the study requirements forparticipation according to the investigator's judgement.