This is a single-center, open-label, prospective study enrolling high-risk (tumor diameter > 4 cm) relapsed/refractory B-NHL patients ineligible for HDCT and ASCT. The treatment consists of ATRA combined with zanubrutinib ± radiotherapy and CAR-T therapy. Based on the efficacy at day 28 post-CAR-T infusion, patients achieving CR will receive 3 months of ATRA and zanubrutinib, while those with PR will receive 3 months of zanubrutinib plus 2 years of ATRA and a PD-1 inhibitor. Patients with stable disease or progression will discontinue. The primary endpoint is the 3-month CR rate following CAR-T infusion.

Inclusion Criteria:

• Willingly sign the informed consent form.

• Age ≥ 18 years, any gender.

• Histologically confirmed as B-cell non-Hodgkin lymphoma, including:

  • Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (DLBCL-NOS)
  • Transformed follicular lymphoma (tFL)
  • High-grade B-cell lymphoma (HGBL) with MYC, BCL2, and/or BCL6 rearrangements
  • High-grade B-cell lymphoma not otherwise specified (HGBL-NOS)
  • Primary mediastinal large B-cell lymphoma (PMBL)
  • Follicular lymphoma grade 3b (FL3b)

• Patients must have experienced at least one line of treatment for relapsed or refractory disease, meeting the following definitions:

  • Refractory: At least partial response (PR) after the last chemotherapy or relapse within 12 months after autologous transplantation.
  • Relapsed: Complete response (CR) after the last chemotherapy, followed by relapse before enrollment, or relapse or progression 12 months or longer after autologous transplantation.

• Maximum tumor diameter (long axis) > 4 cm.

• Evaluator determines that the patient does not meet HDCT/ASCT criteria and meets at least one of the following:

  • Age ≥ 60 years
  • ECOG score = 2
  • FEV1% or DLCO% ≤ 60%
  • LVEF < 50%
  • Creatinine clearance < 60 mL/min
  • ALT or AST > 2× upper limit of normal (ULN)
  • Patient unwilling to receive high-dose chemotherapy and autologous stem cell transplantation.

• Measurable target lesions: lymph nodes ≥ 15 mm in longest diameter, or extranodal lesions > 10 mm.

• Expected survival ≥ 12 weeks.

• Laboratory tests must meet the following requirements at screening:

  • Lymphocyte count ≥ 0.1 × 10^9/L
  • Hemoglobin ≥ 80 g/L
  • Platelets ≥ 50 × 10^9/L
  • ALT/AST ≤ 5 × ULN and total bilirubin < 2 × ULN
  • Creatinine clearance ≥ 30 mL/min
  • Lung function: ≤ CTCAE grade 1 dyspnea, and oxygen saturation (SpO2) ≥ 92% in room air.
  • LVEF ≥ 40%

• Patients with primary central nervous system lymphoma are allowed (secondary CNS lymphoma is not allowed).

• Sufficient venous access for apheresis, and no other contraindications for blood cell separation; female participants of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

• History of allergy to any component of the cellular product or study treatment.

• History of allogeneic hematopoietic stem cell transplantation.

• History of organ transplantation.

• Patients with active viral hepatitis requiring treatment, including:

  • Chronic HBV carriers with HBV DNA ≥ 500 IU/mL.
  • Positive HCV RNA in patients with positive HCV antibodies.
  • Positive HIV antibodies (HIV-Ab).
  • Positive Treponema pallidum antibodies (TP-Ab).
  • Elevated CMV DNA or EBV DNA above normal limits.

• Clinical significance of CNS diseases

• Presence of active primary central nervous system lymphoma.

• Prior treatment with other genetically modified T-cell therapies or CAR-T therapies.

• Severe genetic diseases or autoimmune diseases (e.g., systemic lupus erythematosus).

• Thromboembolic events (e.g., myocardial infarction, pulmonary embolism, deep vein thrombosis) within 6 months prior to screening.

• History of malignancies other than the indication for this trial within the last 5 years, except for in situ cancers (e.g., cervical, bladder, breast) or non-melanoma skin cancer.

• Active infections requiring systemic treatment or uncontrolled infections.

• Received lenalidomide, calcineurin inhibitors, chemotherapy (e.g., methotrexate, cyclophosphamide, ifosfamide, nitrogen mustard, or melphalan), mycophenolate, thalidomide, immunosuppressive antibodies (e.g., anti-TNF, anti-IL6, or anti-IL6R), radiation therapy, or any drug that binds FKBP12 (e.g., rapamycin, tacrolimus, everolimus) within 4 weeks prior to PBMC collection.

• Pregnant or breastfeeding women, or men or women of childbearing potential unwilling to use contraception during the trial and for 2 years after RJ CAR-T 002 cell infusion.

• Participation in other drug clinical trials (e.g., new drug trials, registrational studies, investigator-initiated trials) within 4 weeks prior to PBMC collection.

• Researcher's judgment that the patient is unsuitable for the trial (e.g., poor compliance, drug abuse).

• Vaccination with live or attenuated vaccines within 3 months prior to PBMC collection, or expected vaccination during the trial.