Clinical Study of Cord Blood-derived CAR-NK Cells Targeting CD19 in the Treatment of Refractory/Relapsed B-cell NHL

Study Overview
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Brief Summary
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To study the safety and effectiveness of cord blood-derived CAR-NK cells targeting CD19 in patients with B-cell non-Hodgkin's lymphoma

Detailed Description
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This is an open, single-arm, single-dose, dose-escalation clinical trial designed to evaluate the safety and the preliminary efficacy of CB CAR-NK019 cells. 9-18 patients are planned to be enrolled in the dose-escalation trial (2×10^6 cells/kg ,3×10^6 cells/kg, 4×10^6 cells/kg) . The primary endpoints are DLT, MTD, and the second endpionts are the overall response rates (CR and PR), overall survival, and progression-free survival. Based on the results in the dose-escalation trial, the recommended dose will be determined. Another 30 patients will be enrolled to estimate the safety and efficacy of CB CAR-NK019 under the best dose.

Official Title
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Clinical Study of Cord Blood-derived CAR-NK Cells Targeting CD19 in the Treatment of Refractory/Relapsed B-cell NHL

Conditions
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B-cell Non Hodgkin Lymphoma

Intervention / Treatment
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* Biological: anti-CD19 CAR-NK


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria: Volunteer to participate in this study and sign an informed consent form; Age 18-75 years old, no gender limit; Histologically diagnosed as diffuse large B-cell lymphoma (DLBCL), transforming follicular lymphoma (TFL), primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL) and other inert B-cells NHL conversion type: Refractory or relapsed DLBCL refers to the failure to achieve complete remission after 2-line treatment; disease progression during any treatment, or disease stable time equal to or less than 6 months; or disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation ； Refractory or relapsed MCL must be resistant to or intolerable to BTK inhibitors; Refractory or relapsed indolent B-cell NHL is the failure or recurrence of third-line treatment; Previous treatment must include CD20 monoclonal antibody treatment (unless the subject is CD20 negative) and anthracyclines; At least one measurable lesion with the longest diameter ≥ 1.5 cm exists; The expected survival period is ≥12 weeks; The puncture section of the tumor tissue was positive for CD19 expression; ECOG score 0-2 points; Sufficient organ function reserve: Alanine aminotransferase, aspartate aminotransferase ≤ 2.5× UNL (upper limit of normal value); Creatinine clearance rate (Cockcroft-Gault method) ≥60 mL/min; Serum total bilirubin and alkaline phosphatase ≤1.5× UNL; Glomerular filtration rate>50Ml/min Cardiac ejection fraction (EF) ≥50%; Under natural indoor air environment, basic oxygen saturation>92% Allow a previous stem cell transplantation The approved anti-B-cell lymphoma treatments, such as systemic chemotherapy, systemic radiotherapy, and immunotherapy, have been completed for at least 3 weeks before the study medication; Allow patients who have previously received CAR-T cell therapy and have failed or relapsed after 3 months of evaluation; Female subjects of childbearing age must have a negative pregnancy test and agree to take effective contraceptive measures during the trial Two tests for the new coronavirus were negative. Exclusion Criteria: Those who have a history of allergies to any of the ingredients in cell products; History of other tumors Previously presented with II-IV degree (Glucksberg criteria) acute GvHD or extensive chronic GvHD; or are receiving anti-GvHD treatment; Have received gene therapy in the past 3 months; Active infections that require treatment (except for simple urinary tract infections and bacterial pharyngitis), but preventive antibiotics, antiviral and antifungal infection treatments are allowed; Hepatitis B (HBsAg positive, but HBV-DNA <103 is not an exclusion criterion) or hepatitis C virus infection (including virus carriers), syphilis and other subjects with acquired and congenital immunodeficiency diseases, including But not limited to people living with HIV; According to the New York Heart Association's Heart Function Classification Standard, it is classified as Grade III or Grade IV. Impaired subjects; Those who have received anti-tumor therapy in the early stage but the toxic reaction has not recovered (the CTCAE 5.0 toxic reaction has not recovered to ≤1, except for fatigue, anorexia, and hair loss); Subjects with a history of epilepsy or other central nervous system diseases; Enhanced CT or MRI of the head showed evidence of central nervous system lymphoma; Have received any other drugs that target CD19; Women who are breastfeeding and unwilling to stop breastfeeding; Any other situation that the investigator believes may increase the risk of the subject or interfere with the results of the test.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CB CAR-NK019<br>All subjects were intravenously administrated with CAR-NK019 | Biological: anti-CD19 CAR-NK<br>* lentiviral vector-transducted cord blood-derived NK cells to express anti-CD19 CAR<br>* Other names: CB CAR-NK019;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicity (DLTs) | To evaluate the safety, tolerability, and determine the recommended dosage of cord blood-derived Anti-CD19 CAR-NK Cell Therapy for B-cell Non-Hodgkin Lymphoma | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CR) | To determine the anti-tumor effectivity of CB CAR-NK019 | Up to 2 years | 
| Progression free survival (PFS) | To determine the anti-tumor effectivity of CB CAR-NK019 | Up to 2 years | 
| Duration of response (DOR) | To determine the anti-tumor effectivity of CB CAR-NK019 | Up to 2 years | 
| Overall survival (OS) | To determine the anti-tumor effectivity of CB CAR-NK019 | Up to 2 years | 
| Partial response rate (PR) | To determine the anti-tumor effectivity of CB CAR-NK019 | Up to 2 years | 
| Overall response rate (ORR) | To determine the anti-tumor effectivity of CB CAR-NK019 | Up to 2 years | 
| Immunogenicity after the infusion of CB CAR-NK019 | To evaluate the immunogenicity of CB CAR-NK019 | Up to 2 years |