F01 in the Treatment of Relapsed/Refractory Non-hodgkin's Lymphoma

Inclusion Criteria:

1. Age ≥18 years old, gender unlimited.
2. ECOG score 0-2 points.
3. Large B-cell lymphoma or follicular lymphoma grade 3b was confirmed byhistopathology.Large B-cell lymphomas include the following types as defined byWHO2016:

• Diffuse large B lymphoma (DLBCL), non-specific type (NOS);
• Large B-cell lymphoma rich in T cells/histiocytic cells;
• EBV positive DLBCL, non-specific type (NOS);
• Primary mediastinal (thymus) large B-cell lymphoma;
• High-grade B-cell lymphoma, non-specific type (NOS) and high-grade B-celllymphoma with MYC and BCL2 or BCL6 rearrangement;
• Follicular lymphoma or other inert lymphoma transformed DLBCL.

4. Must have been previously treated with at least 2-line systemic anti-B-cell lymphoma.Participants must have received at least one course of anthracycline-basedchemotherapy (except when absolutely contraindicated due to cardiac dysfunction) andat least one course of anti-CD20 immunotherapy (except in CD20-negative subjects orcontraindicated due to severe toxicity).

• Induction + consolidation + transplantation + maintenance treatment is a one-linesystem of treatment;
• Anti-CD20 monotherapy does not count as 1-line systemic therapy;
• Local radiotherapy does not count as 1-line systemic therapy.

5. Patients who have previously received targeted CD19 therapy (including monoclonalantibody, double antibody, CAR-T, experimental therapy, etc.) should providehistophistological reports during screening stage to confirm that CD19 expression isstill present in lymphoma tissues after the last targeted CD19 therapy.
6. Imaging evidence indicates recurrent or refractory disease.

• Definition of relapse: partial response (PR) or above achieved after the lasttreatment, with disease progression after treatment (except for those who meetthe definition of refractory);
• Refractory is defined as the failure to achieve a partial response (PR) or abovefrom the last treatment, or relapse within 6 months after the last treatmentregimen, or relapse within 12 months after autologous hematopoietic stem celltransplantation (ASCT). (If salvage therapy is performed after ASCT, subjectsmust have a response < PR to terminal therapy.).

7. According to Lugano 2014 lymphoma efficacy evaluation criteria (Cheson 2014), there isat least one measurable lesion (a measurable lesion is defined as a lymph node lesionwith a diameter greater than 1.5cm and an extra-lymph node lesion with a diametergreater than 1.0cm).

• Lesions that have previously received radiotherapy are only considered measurable ifthere is clear evidence of disease progression after completion of radiotherapy.

8. The expected survival is greater than 3 months.
9. Blood routine within 7 days from eluvial pre-treatment chemotherapy should meet thefollowing requirements:

• Absolute value of neutrophil (ANC) ≥ 1.0×109/L;
• Hemoglobin (Hb) ≥ 80g/L;
• Platelet count (PLT) ≥ 50×109/L.

10. Adequate liver, kidney, lung and heart function, defined as:
11. Serum ALT and AST ≤ 2.5 times the upper limit of normal;
12. Total bilirubin ≤ 1.5 times the upper limit of normal, except those with Gilbertsyndrome, whose total bilirubin must ≤ 3.0 times the upper limit of normal;
13. Creatinine clearance (estimated by Cockcroft Gault formula) (Appendix 2) ≥60ml/min;
14. Under indoor ventilation conditions, the blood oxygen saturation in thenon-oxygen state is ≥ 92%; There was no clinically significant pleural effusion;
15. Left ventricular ejection fraction ≥ 50%; Echocardiography confirmed noclinically significant pericardial effusion. No clinically significantabnormalities were found in the ECG.
16. Subjects receiving hematopoietic growth factor support therapy, includingerythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocytemacrophage-colony-stimulating factor (GM-CSF), and platelet agonist (TPO), There mustbe a 2-week interval between the last growth factor support treatment and thescreening period evaluation; Screening platelet assessment should be at least 1 weekaway from the last platelet transfusion, and screening hemoglobin assessment should beat least 2 weeks away from the last red blood cell transfusion.
17. During the screening period, the serum pregnancy test results of fertile femalesubjects must be negative (women who have been surgically sterilized or have beenmenopausal for at least 2 years are considered not fertile). Fertile female subjectsand male subjects must use highly effective contraceptive methods throughout theclinical study period and within 1 year after the last study treatment; At the sametime, a commitment should be made not to donate eggs (egg cells, oocytes)/sperm forassisted reproduction within 1 year after the last study treatment.
18. Voluntarily participate in clinical trials and sign informed consent.

Exclusion Criteria:

1. Subjects with known allergic reactions, hypersensitivities, intolerances, orcontraindications to F01 or any component of the drugs that may be used in the study,including fludarabine, cyclophosphamide, and tocilizumab, or who have previouslyexperienced severe allergic reactions.
2. Primary central nervous system lymphoma.
3. Subjects with gastrointestinal lymphoma who had a history of ≥ grade 3gastrointestinal bleeding in the 3 months prior to screening and those at risk ofdeveloping ≥ grade 3 gastrointestinal bleeding as assessed by investigators (CTCAE,version 5.0).
4. Subjects with a history of central nervous system lymphoma, lymphoma cells found incerebrospinal fluid, and previous imaging findings of intracranial involvement oflymphoma could not be enrolled.
5. Performed allogeneic hematopoietic stem cell transplantation.
6. Autologous hematopoietic stem cell transplantation was performed within 3 monthsbefore eluvial pre-treatment chemotherapy.
7. Subjects who have previously received CD19-targeted CAR-NK therapy; The best efficacyof previous targeted CD19 CAR-T therapy < PR.
8. Major surgery or live vaccination within 28 days prior to screening.
9. Received the following anti-tumor therapy within the specified time frame beforeeluvial pre-treatment chemotherapy:
10. Received small molecule targeted therapy within 3 weeks or 5 half-lives (whichever is longer);
11. Receiving large molecule drug therapy within 4 weeks or 5 half-lives, whicheveris longer (4 weeks for anti-CD20 antibody);
12. Received cytotoxic therapy or modern Chinese medicine with anti-tumor effectswithin 3 weeks (liposomal adriamycin washout period was 4 weeks);
13. Have received experimental therapy within 4 weeks (except for explicit placebocontrol);
14. Received local palliative radiotherapy within 2 weeks.
15. At the time of screening, any aes associated with previous anti-lymphoma therapy havenot returned to ≤ grade 1 or baseline (CTCAE version 5.0) (except for hair loss, bloodroutine and blood biochemical related AEs; Blood routine and blood biochemical testvalues refer to the inclusion criteria Article 9 and 10).
16. Previous CNS disease, such as seizures, cerebrovascular accidents (ischemia/bleeding),dementia, cerebellar disease, or any CNS related autoimmune disease.
17. At the time of screening, confirmed systemic autoimmune diseases requiring maintenancetreatment or confirmed systemic autoimmune diseases were in the active phase.
18. Unstable cardiovascular function:
19. Myocardial infarction occurred within 6 months prior to screening;
20. Unstable angina occurred within 3 months prior to screening;
21. Uncontrolled, clinically significant arrhythmias (e.g., persistent ventriculartachycardia, ventricular fibrillation, torsades de pointes arrhythmia );
22. Mobitz II degree II or III degree atrioventricular block;
23. New York Heart Function Society classification ≥3 congestive heart failure;
24. Poorly controlled hypertension (systolic blood pressure > 160 mmHg and/ordiastolic blood pressure > 100 mmHg) or accompanied by hypertensive crisis orhypertensive encephalopathy;
25. Active hepatitis B virus (HBV), hepatitis C virus (HCV) infection at screening time.Admission of HBsAg positive and/or HBcAb positive but HBV-DNA negative, and/or HCVAbpositive but HCV-RNA negative subjects (if the study center report includes areference value range, the upper limit of normal HBV-DNA and HCV-RNA testing is basedon the test values at each study center). Higher than the upper limit of the detectionvalue is defined as "positive"; If the research center report only shows "negative/positive", "positive" is subject to the test report result).
26. Known serum HIV-positive or active HIV infection history, and syphilis screeningantibody positive.
27. There is an active, uncontrolled infection that requires intravenous treatment withantibiotics, antiviral or antifungal agents within 14 days prior to eluvialpre-treatment chemotherapy; However, these drugs can be used for preventive treatment (including intravenous medication).
28. Malignant tumors that require treatment or have evidence of recurrence within 2 yearsprior to screening (except non-melanoma skin cancer that has been surgically removed,cured cervical carcinoma in situ, localized prostate cancer, low-stage bladder cancer,and ductal carcinoma in situ of the breast). However, subjects with tumors that hadreceived >2 years of prior radical therapy and had no evidence of recurrence wereadmitted.
29. Use of drug combinations/combination therapies expressly prohibited by the protocolduring screening.
30. The investigator believes that there is any life-threatening disease, medicalcondition, or organ system dysfunction that may affect the subject's safety or studycompliance.