Safety and Efficacy of Metabolically Armed CD19 CAR-T Cells (Meta10-19) in the Treatment of r/r B-NHL Clinical Research

Inclusion Criteria:

• All subjects or guardians must sign an informed consent form approved by the EthicsCommittee in person before commencing any screening process;

• Age > 18 years old, ≤ 70 years old, male or female;

• Diagnosis of relapsed/refractory (R/R) indolent B-cell lymphoma, and/or R/R diffuselarge B-cell lymphoma (DLBCL). Refractory diseases are defined as one of thefollowing：

1. Patients with relapsed or refractory B-cell lymphoma treated with one standardtreatment regimen and one salvage regimen treated with rituximab or anotherCD20 antibody drug and at least two treatment regiments appropriate for theirdisease, one of which should include anthracyclines;

2. After treatment with these regimens, patients maintain SD (SD duration ≤ 12months) or still progress；

3. Recurrence after autologous hematopoietic stem cell transplantation, orrecurrence of allogeneic HSCT, or inability to accept HSCT for various reasons；

4. Patients with double-strike or triple-strike B-cell lymphoma who did notrespond to second-line therapy；

• CD19 expression was positive by immunohistochemistry or flow cytometry (accept theresults of this peripheral blood mononuclear cells or previous report from a Class Atertiary hospital before peripheral blood collection);

• If the subject has progressed or relapsed after prior CD19 CAR-T cell therapy, theplanned apheresis phase should be at least 1 month after that, or the subject hasbeen treated with other biologics, but is in the washout period;

• At least one measurable lesion at baseline, according to the Preliminary Assessment,staging and Response Assessment recommendations for Hodgkin's and non-Hodgkin'slymphoma (2014 edition);

• Expected survival time greater than 12 weeks;

• ECOG score 0-1 (subjects with central nervous system diseases caused by leukemia orlymphoma need to be determined by the investigator);

• Organ function：

1. Complete blood count (CBC) test [the following criteria should be met within 24hours prior to apheresis, and supportive treatment such as transfusion,platelet transfusion, cell growth factor (except recombinant erythropoietin)should be avoided within 7 days prior to detection]

• Lymphocyte count ≥ 0.5×109/L (except for those receiving bridgingchemotherapy);
• Platelet count ≥ 25×109/L;
• Hemoglobin ≥ 70.0 g/L

2. Blood Biochemistry:

• Serum creatinine (Scr) ≤ 1.5 x ULN, or
• endogenous creatinine clearance ≥ 40 mL/min (using Cockcroft-Gaultformula);
• alanine aminotransferase (ALT) ≤ 2.5 x ULN;
• aspartate aminotransferase (AST) ≤ 2.5 ×ULN;
• Total bilirubin (TBIL) ≤ 2 ×ULN; Subjects with total bilirubin < 3 × ULNand direct bilirubin < 1.5× ULN with Gilbert-.Meulengracht syndrome couldbe included;
• Serum lipase and amylase ≤ 1.5×ULN;
• Alkaline phosphatase (ALP) ≤ 2.5 ×ULN;
• In case of bone or liver metastasis, AST, ALT and ALP ≤ 5 ×ULN;
• Prothrombin time (PT) extended ≤ 4 s, fibrinogen ≥ 1 g/L, activatedpartial thromboplastin time (APTT) ≤ 1.5 ×ULN;

3. Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) > 91% in indoor air environment..

• Hemodynamic stability was determined by echocardiography or multichannelradionuclide angiography (MUGA) and LVEF ≥45％;

• Patients using the following drugs must meet the following conditions:

1. Steroid: Therapeutic doses of steroids must be discontinued 2 weeks prior toMeta10-19 infusion. However, physiological replacement doses of steroids arepermitted, hydrocortisone or its equivalent < 6-12mg/mm2/ day；

2. Immunosuppressive agent: Any immunosuppressive drug must be stopped ≥4 weeksbefore the informed consent is signed;

3. Stop all anti-proliferation therapies other than preconditioning chemotherapyin the 2 weeks before Meta10-19 infusion；

4. Treatment for CNS disease must be stopped 1 week before Meta10-19 infusion (e.g., intrathecal methotrexate)

• The patient has recovered from the toxicity of the previous treatment, that is, theCTCAE toxicity grade is less than 1 (The exception is specific toxicity of grade 2or less, such as hair loss, which the researchers have determined is not recoverablein a short period of time) is suitable for pretreatment chemotherapy and CAR-T celltherapy;

• Women of childbearing age and all male patients must consent to use a effectivecontraception for at least 12 months after Meta10-19 infusion and until twoconsecutive PCR tests show no more CAR T cells in vivo.

Exclusion Criteria:

• Patients with present or history of central nervous system diseases not associatedwith leukemia or lymphoma， such as seizures disorder, cerebrovascularischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease withCNS involvement;

• Patients who had received chemotherapy other than preconditioning chemotherapywithin 2 weeks prior to Meta10-19 infusion;

• Patients who participated in other clinical trials within 30 days prior toenrollment;

• Patients with active hepatitis B (defined as hepatitis B surface antigen positive orhepatitis B core antibody positive, concomitant hepatitis B virus DNA level > 1000copies/ml) or hepatitis C (HCV RNA positive);

• Patients with HIV antibody positive or treponema pallidum antibody positive;

• Patients with uncontrolled acute life-threatening bacterial, viral or fungalinfections (e.g. positive blood cultures ≤72 hours before Meta10-19 infusion);

• History of unstable angina and/or myocardial infarction within 6 months prior tosigning the informed consent; History of uncontrolled thrombotic events, majorbleeding, or deep venous thrombosis (DVT) within 12 months prior to signing theinformed consent;

• Patients with history of other malignancies, but the following conditions can beenrollment:

1. Adequately treated basal or squamous cell carcinoma (requiring adequate woundhealing before signing informed consent);

2. Carcinoma in situ (DCIS) of cervical or breast cancer, which has been treatedtherapeutically, has shown no signs of recurrence for at least 3 years prior tothe signing of the informed consent；

3. The primary malignancy has been completely resected and in complete remissionfor ≥5 years；

• Women who are pregnant or breastfeeding (pregnancy tests for women of childbearingage are positive);

• History of QT interval prolongation or severe cardiac disease;

• Before signing the informed consent form, the ADA (FMC63) test was significantlypositive (the test result was weakly positive, and it was necessary to discuss withthe investigator whether to rule it out);

• Other conditions that the investigator considered should not be enrolled in thisclinical study.