The trial is a single arm, single-center, non-randomized phase I clinical trial which is designed to evaluate the safety and efficacy of C-CAR039 in treatment of relapsed or refractory NHL patients

This study plans to enroll 25 patients to assess the safety and efficacy of C-CAR039. Subjects who meet the eligibility criteria will receive a single dose of C-CAR039 injection.

The study will include the following sequential phases: Screening, Apheresis and C-CAR039 manufacturing, Bridging (if needed), Baseline, lymphodepletion, C-CAR039 infusion, and Follow-up Visit.

Inclusion Criteria:

• 1. Volunteered to participate in this study and signed informed consent
• 2. Age 18-75 years old, male or female
• 3. CD19 or CD20 positive DLBCL (including PMBCL and tFL), FL and MCL confirmed by cytology or histology according to WHO2016 criteria. For CD20-positive subjects, they should have received at least one regimen containing anti-CD20-targeted therapy (such as rituximab). If they do not complete the regimen due to intolerance, the cause should be recorded.
• 4. Relapsed or refractory disease after ≥ 2 lines (for FL, at least 3 lines) of standard therapy or relapsed after autologous stem cell transplantation (ASCT)
• 5. At least one measurable lesion (LDi ≥ 1.5 cm);
• 6. At least two weeks from last treatment (radiation, chemotherapy, mAb, etc) to apheresis;
• 7. LVEF≥ 50% (ECHO)
• 8. No active pulmonary infections, normal or mild impaired pulmonary function and SpO2≥92%
• 9. Laboratory criteria: ANC≥1.0×109/L; Platelets≥50×109/L; Serum total bilirubin ≤1.5x ULN; Creatinine≤ ULN; AST and ALT≤3x ULN
• 10. No contraindications of apheresis;
• 11. Expected survival ≥ 3months
• 12. ECOG score 0 or 1

Exclusion Criteria:

• 1. Have a history of allergy to cellular products;

• 2. According to the NYHA cardiac function grading standards, patients with grade III or IV cardiac dysfunction;

• 3. A history of craniocerebral trauma, disturbance of consciousness, epilepsy, cerebrovascular ischemia, cerebrovascular hemorrhagic disease, etc.;

• 4. Patients with central nervous system involvement;

• 5. Patients with autoimmune diseases, immunodeficiency or other conditions requiring immunosuppressive therapy;

• 6. Received allogeneic hematopoietic stem cell transplantation before;

• 7. Previous use of any CAR T cell product or other genetically modified T cell therapy;

• 8. Autologous stem cell transplantation within 6 weeks before infusion;

• 9. Severe active infections (except for simple urinary tract infections, bacterial pharyngitis), or currently undergoing intravenous infusion of antibiotics. However, prophylactic antibiotic, antiviral and antifungal infection treatments are permissible;

• 10. Live vaccination within 4 weeks prior to apheresis;

• 11. People infected with HIV, HBV, HCV and TPPA/RPR, and carriers with HBV;

• 12. A history of alcohol abuse, drug use or mental illness;

• 13. Subjects who are not sterilized and have any of the following conditions:

  1. are pregnant/lactating; or
  2. planned pregnancy during the trial; or
  3. being fertile and unable to use effective contraception;

• 14. Severe hypersensitivity to fludarabine or cyclophosphamide;

• 15. A history of other primary cancers other than the following:

  1. Non-melanoma tumors such as basal cell carcinoma of the skin that are cured by excision
  2. Cured in situ cancers such as cervical, bladder, or breast cancer

• 16. The investigators consider that the subject has other conditions that are not suitable for this trial.