In this single-center, single-arm, prospective, Phase 1/2 study, the safety and efficacy of autologous BCOR and ZC3H12 genes knock-out CD19-targeting chimeric antigen receptor (CAR) T-cell therapy will be evaluated in patients with refractory/relapsed (r/r) B-cell Lymphoma. For simplicity, we have termed these CD19 CAR T cells lacking ZC3H12A and BCOR as CAR19TIF( immortal-like and functional CD19 CAR T ) cells, reflecting their immortal-like and functional characteristics.

In phase 1, 3 eligible patients will be enrolled and receive CAR19TIF cells at a initial dose of 5×10^5 cells/kg. Based on the results, subsequently an additional 3-15 patients will be enrolled in a "3+3" dose-escalation/decline design to adjust the dose of CAR19TIF cells to achieve optimal safety and efficacy. The recommended Phase 2 dose (RP2D) will then be established. 10 to 12 subjects will be enrolled and receive CAR19TIF cells infusion at dose of RP2D.

Phase 1 (dose escalation/decline)

In phase 1, 6-18 subjects will be enrolled. Referring to the starting dose of most CAR-T cell therapies, and to avoid exposing patients to the risk of "ineffective expansion dose", 3 patients will receive CAR19TIF cells therapy at a starting dose of 5×10^5 cells/kg.According to the copy number of CAR-T cells were assessed by number in peripheral blood and clinical efficacy data, additional 3-15 patients will be enrolled in a "3+3" dose-escalation/decline design to adjust the dose of CAR19TIF cells to achieve optimal safety and efficacy :

After obtaining effective expansion data and clinical efficacy data, a descending dose escalation model will be adopted: such as 1×10^5 cells/kg, 5×10^4 cells/kg. If the 5×10^5 cells/kg dose group does not achieve efficient expansion and clinical benefit, an ascending dose escalation model will be adopted, such as 2×10^6 cells/kg, 6×10^6 cells/kg.

3 subjects are enrolled in a cohort corresponding to a dose level. If 1 subject in a cohort of 3 subjects experiences a DLT, 3 additional subjects will be enrolled at the current dose level.

For safety purposes, the administration of CAR19TIF cells will be staggered by 28 days between the first two subjects in each cohort. And for each of the remaining cohorts, the administration of CAR19TIF cells will be staggered by 28 day.

Phase 2 (expansion cohort) In phase 2, 10 to 12 subjects will be enrolled and receive cell infusion at dose of RP2D, which will be determined based on the maximum tolerated dose (MTD), occurrence of DLT, the obtained efficacy results, pharmacokinetics/pharmacodynamics and other data according to the phase 1.

Objectives The primary objectives of the phase 1 were to evaluate the tolerability and safety of CAR19TIF cells in patients with r/r B-cell Lymphoma

, and determine RP2D. The primary purpose of the phase 2 study was to evaluate the efficacy of CAR19TIF cells in the above population.

Inclusion Criteria:

1. Age 18-70 (inclusive).

2. Subjects who meet the following requirements:

   2.1 Histologically confirmed refractory/relapsed B cell Non-Hodgkin's lymphomas (NHL), including the following types defined by World Health Organization (WHO) 2016:

   • Diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS);
   • Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
   • Transformed follicular lymphoma (TFL);
   • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
   • Follicular lymphoma (FL);
   • Mantle cell lymphoma (MCL) (pathologically confirmed, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1);
   • Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.

   2.2 Relapsed disease is defined as disease progression (PD) after achieving disease remission (including CR and PR) with the latest standard regimen.

   2.3 Refractory disease is defined as no CR to first-line therapy: Evaluation of PD (never reached response or SD) after standard first-line treatment, or

   • SD as best response after at least 4 cycles of first-line therapy (eg,4 cycles of R-CHOP), or
   • PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or
   • Refractory post-autologous stem cell transplant (ASCT): i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals); ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy.

   2.4 Individuals who are intolerant to standard treatment can also be included in the study in the investigator's judgment.

3. Individuals must have received adequate prior therapy:

   3.1 For MCL, prior therapy must have included:

   • Anthracycline or bendamustine-containing chemotherapy and
   • Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
   • Bruton's tyrosine kinase inhibitor (BTKi). 3.2 For other types, prior therapy must have included:
   • Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
   • Anthracycline containing chemotherapy regimen. 3.3 For individual with transformed FL must have relapse or refractory disease after transformation to DLBCL.

4. At least 1 measurable lesion: lymph node site with a long axis >1.5cm, extranodal site with a long axis >1.0cm (according to the Lugano2014 criteria). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.

5. CD19 positive (detected by immunohistochemistry [IHC]).

6. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for hematological toxicities and clinically non-significant toxicities such as alopecia).

7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

8. Absolute neutrophil count (ANC) ≥ 1 x 10^9/L, Platelet count ≥50 x 10^9/ L, hemoglobin (Hgb) ≥ 80g/L (hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions above).

9. Adequate renal, hepatic, pulmonary and cardiac function defined as:

   9.1 Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min.

   9.2 Serum alanine aminotransferase / aspartate aminotransferase (ALT/ AST) ≤ 3 upper limit of normal (ULN); Total bilirubin ≤ 1.5 ULN, except in subjects with 3) Gilbert's syndrome.

   9.3 Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings.

   9.4 Coagulation Function: International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN.

   9.5 Baseline oxygen saturation >91% on room air.

10. Subjects of both genders who are willing to practice birth control from the time of consent through 6 months after the completion of conditioning chemotherapy. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).

11. Voluntarily participate in this clinical trial and sign an informed consent form.

Exclusion Criteria:

1. Expected survival time < 3 months per Principal Investigator's opinion.

2. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.

3. History of allogeneic hematopoietic stem cell transplantation, or organ transplantation.

4. Prior CD19 targeted therapy.

5. Patients who have used any of the following agents or treatments within a specific period of time:

   5.1 Received any chemotherapy drugs or small molecule targeted drugs within 2 weeks prior to lymphodepletion; 5.2 Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecific antibodies within 3 weeks prior to lymphodepletion; 5.3 Received radiotherapy within 6 weeks prior to lymphodepletion. However, if disease progressed at the site of radiotherapy, or if there are positive lesions detected by PET-CT at non-radiotherapy sites, enrollment is allowed.

6. Prior CAR-T therapy or other genetically modified T cell therapy.

7. Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma.

8. History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of CAR19TIF cells.

9. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.

10. Uncontrolled or active infectious diseases, such as human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B or C, epstein-barr virus (EBV), and cytomegalovirus (CMV) infection.

11. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.

12. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.

13. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.

14. Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).

15. Primary immunodeficiency.

16. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.

17. History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic anticoagulation within 6 months of enrollment.

18. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.

19. History of severe immediate hypersensitivity reaction to any of the agents used in this study.

20. Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.

21. In the investigator's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.