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

This is a single arm, open-label study. This study is indicated for relapsed or refractory CD19+ Diffuse Large B-Cell Lymphoma. The selections of dose levels and the number of subjects are based on clinical trials of similar foreign products.

• Main research objectives:

To evaluate the safety and efficacy of metabolically armed CD19 CAR-T Cells in the treatment of r/r DLBCL.

• Secondary research objectives:

• To evaluate the pharmacokinetic (PK) and pharmacodynamics(PD) characteristics of metabolically armed CD19 CAR-T Cells after infusion.
• To evaluate tumor remission after infusion of metabolically armed CD19 CAR-T Cells.

Inclusion criteria

• The patient or his/her guardian voluntarily signed the informed consent
• Adult Patients clinical diagnosis of relapsed and refractory diffuse large B-cell lymphoma (Primary mediastinal large B-cell lymphoma and transformed follicular lymphoma are included)

Definition of refractory:

• No response to the last treatment, including:

The best response to the last treatment was PD, or ; The best response to the last treatment was SD and the duration was not more than 6 months after the last dose.

• Not suitable for autologous hematopoietic stem cell transplantation (ASCT), or ASCT refractory, including:

Disease progression or recurrence within 12 months or less (recurrence must be confirmed by biopsy) after ASCT treatment, or; Patients accept remedial treatment after ASCT must have no response or relapse after the last treatment

• Patients who had previously received ≥2 lines therapy including at least:

• A chemotherapy regimen containing anthracyclines
• For patients with transformed DLBCL from follicular lymphoma, they must have previously received chemotherapy for follicular lymphoma and have refractory disease after transformation to DLBCL.
• Patients with double-strike and triple-strike lymphoma who do not respond to second-line treatment, where double-strike/triple-strike is defined as:

Detection of lymphoma cells with C-MYC gene translocation accompanied by BCL-2 gene translocation or/and BCL-6 gene translocation by chromosome or FISH technology.

• CD19 expression was positive by immunohistochemistry or flow cytometry (accept the results of this peripheral blood mononuclear cells or previous report from a Class A tertiary hospital before peripheral blood collection)
• At least one measurable lesion at baseline, according to the initial assessment, staging and Response Assessment recommendations for Hodgkin's and non-Hodgkin's lymphoma (2014 edition)
• Expected survival time greater than 12 weeks
• The baseline ECOG score was 0 or 1
• Organ function:

• Kidney function is defined as:

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 result was ×0.742]

• Liver function is defined as:

ALT≤5 times ULN, and; Patients with total bilirubin ≤2.0mg/dl, except those with Gilbert-Meulengracht syndrome. Patients with Gilbert-Meulengracht syndrome with total bilirubin ≤3.0 times ULN and direct bilirubin ≤1.5 times ULN were included

• Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) ≥91% in indoor air environment.
• Hemodynamic stability was determined by echocardiography or multichannel radionuclide angiography (MUGA) and LVEF ≥45%
• Patients using the following drugs must meet the following conditions:

• Steroid: Therapeutic doses of steroids must be discontinued 2 weeks prior to Meta10-19 infusion. However, physiological replacement doses of steroids are permitted, hydrocortisone or its equivalent <6-12mg/mm2/ day
• Immunosuppressive agent: Any immunosuppressive drug must be stopped ≥4 weeks before the informed consent is signed
• Anti-proliferative therapy in addition to preconditioning chemotherapy 2 weeks prior to Meta10-19 infusion
• 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, the CTCAE toxicity grade is less than 1 (The exception is specific toxicity of grade 2 or less, such as hair loss, which the researchers have determined is not recoverable in a short period of time) is suitable for pretreatment chemotherapy and CAR T cell therapy
• Women of childbearing age and all male patients must consent to use a effective contraception for at least 12 months after Meta10-19 infusion and until two consecutive PCR tests show no more CAR T cells in vivo

Exclusion criteria

• Patients with present or history of central nervous system diseases such as seizures disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
• Patients with history of allogeneic hematopoietic stem cell transplantation
• Patients who had received chemotherapy other than preconditioning chemotherapy within 2 weeks prior to Meta10-19 infusion
• Patients who participated in other clinical trials within 30 days prior to enrollment
• Patients with active hepatitis B (defined as hepatitis B surface antigen positive or hepatitis B core antibody positive, concomitant hepatitis B virus DNA level >1000 copies/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 fungal infections (e.g. positive blood cultures ≤72 hours before Meta10-19infusion)
• Patients with unstable angina pectoris and/or myocardial infarction within 6 months prior to enrollment
• Patients with history of other malignancies, but the following conditions can be enrollment:

• Adequately treated basal or squamous cell carcinoma (requiring adequate wound healing before signing informed consent);
• Carcinoma in situ (DCIS) of cervical or breast cancer, which has been treated therapeutically, has shown no signs of recurrence for at least 3 years prior to the signing of the informed consent
• The primary malignancy has been completely resected and in complete remission for ≥5 years
• Women who are pregnant or breastfeeding (pregnancy tests for women of childbearing age are positive)
• Patients with active neuroautoimmune or inflammatory conditions (e.g. Guillian-Barre syndrome, amyotrophic lateral sclerosis);
• Other conditions that the investigator considered should not be enrolled in this clinical study, such as poor compliance.