Inclusion Criteria:
1. Voluntary participation; full understanding of the study and provision of written informed consent obtained before any study-related procedure not part of standard care; willingness to comply with follow-up.
2. Age 18-75 years; either sex.
3. ECOG performance status 0-1.
4. Histologically confirmed large B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, or indolent lymphoma transformed to DLBCL; CD19 and/or CD20 positive.
5. At least one measurable lesion per Lugano criteria: nodal lesion longest diameter \>1.5 cm, extranodal lesion \>1.0 cm.
6. Prior treatment response must meet one of the following:
• Large B-cell lymphoma, grade 3B follicular lymphoma, transformed indolent lymphoma: i. Primary refractory and ineligible/unable to receive autologous CAR-T: best response PD after ≥2 cycles of first-line therapy, or SD after ≥4 cycles.
ii. Relapse ≤12 months after achieving CR with first-line chemo-immunotherapy. iii. Relapse/progression ≤12 months after autologous HSCT. iv. Refractory to, relapsed after, or progressed on ≥2 prior lines (including autologous CAR-T): best response PD or SD after ≥2 cycles of the most recent regimen.
v. Transformed indolent lymphoma: prior chemotherapy for iNHL and ≥1 systemic regimen after transformation, fulfilling the above refractory/relapse criteria.
• Grade 1, 2, or 3A follicular lymphoma: i. Primary refractory and ineligible/unable to receive autologous CAR-T: best response PD after ≥2 cycles of first-line therapy.
ii. Refractory to, relapsed after, or progressed on ≥2 prior lines (including autologous CAR-T): best response PD or SD after ≥2 cycles of the most recent regimen.
• Mantle-cell lymphoma: i. Primary refractory and ineligible/unable to receive autologous CAR-T: best response PD after ≥2 cycles of first-line therapy, or SD after ≥4 cycles.
ii. Refractory to, relapsed after, or progressed on ≥2 prior lines (including autologous CAR-T): best response PD or SD after ≥2 cycles of the most recent regimen.
7. Estimated life expectancy ≥3 months.
8. Screening laboratory values (may be repeated once):
* Hemoglobin ≥8.0 g/dL (no transfusion within 7 days).
* Platelets ≥50×10⁹/L (no transfusion within 7 days).
* ANC ≥1.0×10⁹/L (growth-factor support allowed if none within 7 days of test).
* AST/ALT ≤3×ULN (≤5×ULN if liver involvement).
* Serum creatinine ≤1.5×ULN or CrCl ≥60 mL/min (Cockcroft-Gault).
* Total bilirubin ≤2×ULN (≤3×ULN if liver involvement); except congenital bilirubin disorders (e.g., Gilbert's syndrome: direct bilirubin ≤1.5×ULN).
* INR, PT, APTT \<1.5×ULN.
9. Toxicities from prior anti-cancer therapy (except alopecia, nausea, and the above lab values) must have stabilized at baseline or resolved to ≤Grade 1.
10. WOCBP must have a negative high-sensitivity serum β-hCG pregnancy test at screening and again before the first dose of cyclophosphamide/fludarabine.
11. Subjects of reproductive potential must use effective contraception for ≥12 months after completing study therapy.
Exclusion Criteria:
* Subjects with any of the following conditions are ineligible for this trial:
1. Any malignancy other than B-cell non-Hodgkin lymphoma ever diagnosed or treated, except:
* Malignancy that received curative therapy and has shown no evidence of active disease for ≥2 years before enrolment; or
* Adequately treated non-melanoma skin cancer with no current evidence of disease.
2. Prior anti-cancer therapy within the stated windows (before lymphodepletion):
* CNS prophylaxis (e.g., intrathecal methotrexate and/or cytarabine) within 7 days;
* Cytotoxic chemotherapy or radiotherapy within 14 days;
* Small-molecule targeted or epigenetic therapy within 14 days or 5 half-lives, whichever is longer;
* Monoclonal antibody, bispecific antibody, or antibody-drug conjugate within 21 days or 5 half-lives, whichever is shorter;
* Investigational drug or invasive investigational device within 28 days (if the therapy is also investigational, the 28-day wash-out applies);
* Autologous haematopoietic stem-cell transplant or CD19-directed autologous CAR-T therapy within 100 days.
3. Any autologous cellular or gene therapy other than CD19-directed autologous CAR-T.
4. Any allogeneic cellular (including CAR-T) or gene therapy.
5. Prior allogeneic haematopoietic stem-cell transplantation.
6. Positive donor-specific antibody (DSA).
7. At least one of the following high-risk features:
* Sum of the product of perpendicular diameters (SPD) of all measurable lesions ≥100 cm²;
* Bulky disease: single mass ≥7.5 cm; mediastinal mass with maximum diameter \>1/3 of thoracic diameter;
* Obstructive/compressive emergency (e.g., bowel obstruction, vascular compression) requiring urgent intervention at screening.
8. Active CNS involvement (symptomatic or positive CSF/imaging); subjects with prior CNS disease now in remission (asymptomatic with negative CSF and imaging) are eligible.
9. Significant bleeding diathesis: gastrointestinal bleeding, haemorrhagic cystitis, coagulopathy, hypersplenism (splenomegaly on exam/US, cytopenias, hyperplastic marrow) or ongoing anticoagulation.
10. Chronic concomitant systemic corticosteroids or other immunosuppressants, except: topical, ocular, intra-articular, nasal or inhaled corticosteroids; short-course steroids for prophylaxis (e.g., contrast allergy).
11. Severe underlying medical conditions:
* Active serious viral, bacterial or uncontrolled systemic fungal infection;
* Active systemic autoimmune disease requiring therapy.
12. Significant cardiac disease:
* NYHA class III or IV congestive heart failure;
* Myocardial infarction or CABG within 6 months before enrolment;
* Clinically relevant ventricular arrhythmia or unexplained syncope not vasovagal or dehydration-related;
* Severe non-ischaemic cardiomyopathy;
* Left ventricular ejection fraction (LVEF) \<45% by echo or MUGA within 4 weeks before lymphodepletion.
13. Resting oxygen saturation \<92%.
14. Clinically relevant prior or current CNS disorder: epilepsy, seizure-like episodes, paralysis, aphasia, stroke, severe head trauma, dementia, Parkinson's disease, cerebellar disorder, organic brain syndrome or major psychiatric illness.
15. Live-attenuated vaccine within 4 weeks before screening.
16. Major surgery within 2 weeks before screening or planned within 2 weeks after study treatment (local anaesthesia allowed).
17. Positive screen for HBsAg, HBeAg, HBV DNA, HCV antibody, HCV RNA, or HIV antibody.
18. Life-threatening allergy, hypersensitivity or intolerance to study-drug excipients including, but not limited to, DMSO.
19. Lactating women.
20. Any condition that, in the investigator's opinion, renders the subject unsuitable for the study.
