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

Inclusion Criteria:

1. The patient or his/her guardian voluntarily signed the informed consent；
2. Patients with relapsed and refractory B-cell Acute Lymphoblastic Leukemia. Definition of relapsed or refractory B-ALL (meeting one of the following conditions):
3. 2 or more relapses;
4. Bone marrow relapsed after allo-HSCT and prepared to infuse Meta10-19 more than 6months after allo-HSCT ;
5. CR not achieved after standardized chemotherapy;
6. Philadelphia-chromosome-positive (Ph+) patients who are ineffective or intolerantto first- and second-generation tyrosine kinase inhibitor (TKI) treatments, orwho have contraindications to tyrosine kinase inhibitors;
7. The number of primordial cells (lymphoblast and prolymphocyte) in bone marrow is ≥ 5%
8. CD19 expression was positive by biopsy or flow cytometry (accept the results of thisperipheral blood mononuclear cells collection or previous Class A tertiary hospitalbefore this peripheral blood collection);
9. Expected survival time greater than 12 weeks
10. The baseline ECOG score was 0 or 1；
11. Organ function：
12. Kidney function: Serum creatinine ≤1.5 times ULN, or； The glomerular filtration rate (eGFR)estimated by MDRD formula was ≥60m/min/1.73m2；[eGFR=186×（age）-0.203×SCr-1.154（mg/dl），for females, the resultwas ×0.742]；
13. Liver function： ALT≤5 times ULN, and; Patients with total bilirubin ≤2.0mg/dl,except those with Gilbert-Meulengracht syndrome. Patients withGilbert-.Meulengracht syndrome with total bilirubin ≤3.0 times ULN and directbilirubin ≤1.5 times ULN were included.
14. Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) ≥91% in indoor air environment.
15. Hemodynamic stability was determined by echocardiography or multichannel radionuclideangiography (MUGA) and LVEF ≥45％;
16. Patients using the following drugs must meet the following conditions:
17. 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；
18. Immunosuppressive agent: Any immunosuppressive drug must be stopped ≥4 weeksbefore the informed consent is signed;
19. Anti-proliferative therapy other than preconditioning chemotherapy isdiscontinued within 2 weeks prior to Meta10-19 infusion；
20. Treatment for CNS disease must be stopped 1 week before Meta10-19 infusion (e.g.,intrathecal methotrexate)
21. 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 2 orless, such as hair loss, which the researchers have determined is not recoverable in ashort period of time) is suitable for pretreatment chemotherapy and CAR-T celltherapy;
22. Women of childbearing age and all male patients must consent to use an 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:

1. Patients with isolated extramedullary relapse;
2. Patients with confirmed diagnosis of Burkitt's lymphoma/ leukemia;
3. Patients who had received prophylaxis for CNS leukemia within 1 week prior toMeta10-19 infusion;
4. Patients with present or history of central nervous system diseases such as seizuresdisorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or anyautoimmune disease with CNS involvement;
5. Patients with history of allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 6 months prior to Meta10-19 infusion;
6. Patients who had received chemotherapy other than preconditioning chemotherapy within 2 weeks prior to Meta10-19 infusion ;
7. Patients who participated in other clinical trials within 30 days prior to enrollment;
8. 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);
9. Patients with HIV antibody positive or treponema pallidum antibody positive;
10. Patients with uncontrolled acute life-threatening bacterial, viral or fungalinfections (e.g. positive blood cultures ≤72 hours before Meta10-19 infusion)
11. Patients with unstable angina pectoris and/or myocardial infarction within 6 monthsprior to enrollment；
12. Patients with history of other malignancies, but the following conditions can beenrollment:
13. Adequately treated basal or squamous cell carcinoma (requiring adequate woundhealing before signing informed consent);
14. 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；
15. The primary malignancy has been completely resected and in complete remission for ≥5 years。
16. Women who are pregnant or breastfeeding (pregnancy tests for women of childbearing ageare positive);
17. Patients with active neuroautoimmune or inflammatory conditions (e.g. Guillian-Barresyndrome, amyotrophic lateral sclerosis);
18. Other conditions that the investigator considered should not be enrolled in thisclinical study, such as poor compliance.