TRAC and Power3 Genes Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B-NHL

Inclusion Criteria:

1. Age 18-70 (inclusive).
2. Subjects who meet the following requirements: 2.1 Histologically confirmed refractory/relapsed B cell NHL, including the followingtypes defined by WHO 2016:

• Diffuse large B-cell lymphoma (DLBCL) not otherwise specified;
• 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 ofmonoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/oroverexpress cyclin D1);
• Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-celllymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma. 2.2 Relapsed disease is defined as disease progression (PD) after achieving diseaseremission (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-linetreatment, or
• SD as best response after at least 4 cycles of first-line therapy (eg,4 cycles ofR-CHOP), or
• PR as best response after at least 6 cycles and biopsy-proven residual disease ordisease progression ≤ 6 months of therapy, or
• Refractory post-autologous stem cell transplant (ASCT) i. Disease progression orrelapsed less than or equal to 12 months of ASCT (must have biopsy provenrecurrence 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 oftherapy. 2.4 Individuals who are intolerant to standard treatment can also be included in thestudy 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 isCD20-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 isCD20-negative) and
• Anthracycline containing chemotherapy regimen. 3.3 For individual with transformed FL must have relapse or refractory disease aftertransformation to DLBCL.

4. At least 1 measurable lesion: lymph node site with a long axis >1.5cm, extranodal sitewith a long axis >1.0cm (according to Lugano2014). Lesions that have been previouslyirradiated will be considered measurable only if progression has been documentedfollowing 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 forhematological 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 subjectto 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 (asestimated by Cockcroft Gault) ≥ 60 mL/min. 9.2 Serum alanine aminotransferase / aspartate aminotransferase (ALT/AST) ≤ 3 upperlimit of normal (ULN); Total bilirubin ≤ 1.5 ULN, except in subjects with 3) Gilbert'ssyndrome. 9.3 Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determinedby an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG)findings. 9.4 Coagulation Function: International Normalized Ratio (INR) ≤ 1.5 times the upperlimit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 timesULN. 9.5 Baseline oxygen saturation >91% on room air.
10. Subjects of both genders who are willing to practice birth control from the time ofconsent through 6 months after the completion of conditioning chemotherapy. Females ofchildbearing potential must have a negative serum or urine pregnancy test (females whohave undergone surgical sterilization or who have been postmenopausal for at least 2years 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 3years.
3. Autologous stem cell transplant with therapeutic intent within 3 months of plannedATHENA CAR-T infusion.
4. History of allogeneic stem cell transplantation.
5. Prior CD19 targeted therapy.
6. Patients who have used any of the following agents or treatments within a specificperiod of time: 6.1 Received any chemotherapy drugs or small molecule targeted drugs within 2 weeksprior to lymphodepletion; 6.2 Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecificantibodies within 3 weeks prior to lymphodepletion; 6.3 Received radiotherapy within 6 weeks prior to lymphodepletion. However, if diseaseprogressed at the site of radiotherapy, or if there are positive lesions detected byPET-CT at non-radiotherapy sites, enrollment is allowed.
7. Prior CAR-T therapy or other genetically modified T cell therapy.
8. Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, orwith a history of central nervous system (CNS) lymphoma or primary CNS lymphoma.
9. History of severe, immediate hypersensitivity reaction attributed to lymphodepletiondrugs or any component of ATHENA CAR-T.
10. Presence or suspicion of fungal, bacterial, viral, or other infection that isuncontrolled or requiring intravenous (IV) antimicrobials for management.
11. Uncontrolled or active infectious diseases, such as human immunodeficiency virus (HIV)infection, acute or chronic active hepatitis B or C, epstein-barr virus (EBV), andcytomegalovirus (CMV) infection.
12. History or presence of central nervous system (CNS) disorder such as seizure disorder,cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmunedisease with CNS involvement.
13. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
14. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, orother clinically significant cardiac disease within 12 months of enrollment.
15. Expected or possible requirement for urgent therapy within 6 weeks due to ongoing orimpending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).
16. Primary immunodeficiency.
17. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus)resulting in end organ injury or requiring systemic immunosuppression/systemic diseasemodifying agents within the last 2 years.
18. History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemicanticoagulation within 6 months of enrollment.
19. Any medical condition likely to interfere with assessment of safety or efficacy ofstudy treatment.
20. History of severe immediate hypersensitivity reaction to any of the agents used inthis study.
21. Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.
22. In the investigator's judgment, the subject is unlikely to complete allprotocol-required study visits or procedures, including follow-up visits, or complywith the study requirements for participation.