Clinical Study of Cord Blood-derived CAR NK Cells Targeting CD19/CD70 in Refractory/Relapsed B-cell Non-Hodgkin Lymphoma

Study Overview
=================
Brief Summary
-----------------
To study the safety and efficacy of cord blood-derived CAR-NK cells targeting CD19/CD70 in patients with B-cell non-Hodgkin's lymphoma

Detailed Description
-----------------
This is a single-center, open, one-arm, dose-escalation study to observe the safety and efficacy of cord blood-derived dualCAR-NK19/70 cells in patients with B-cell non-Hodgkin lymphoma.9-18 patients are planned to be enrolled in the dose-escalation trial (2×10^6 cells/kg, 4×10^6 cells/kg, 8×10^6 cells/kg) . Each dose was given once a week for 3 weeks.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
-----------------
Clinical Study of Cord Blood-derived CAR NK Cells Targeting CD19/CD70 in Refractory/Relapsed B-cell Non-Hodgkin Lymphoma

Conditions
-----------------
B-cell Non Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Biological: CB dualCAR-NK19/70


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Voluntarily participate in the study and sign the informed consent; Age 18-75, male and female; Histologically confirmed diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and other inert B-cell NHL transforming types: (1)refractory or recurrent DLBCL and tFL must be approved by 2 line immune disease relapse after chemotherapy treatment; (2) refractory definition large B cell lymphoma (research SCHOLAR - 1 standard) : more than 4 courses first-line immune chemotherapy disease progression; The stable time of the disease is equal to or less than 6 months; Or disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation; (3) refractory or recurrent MCL must be 1 line with immune chemotherapy; BTK inhibitors are resistant or intolerant as 2-line therapy; (4)always treatment must include CD20 single resistance (unless the subjects for CD20 negative) and anthracycline-based; 4. There was at least one measurable lesion with the longest diameter ≥1.5 cm; 5. Predicted survival ≥12 weeks; 6. The expression of CD19 or CD70 in biopsy sections of tumor tissue was positive; 7. ECOG score 0-2; 8. Adequate reserve of organ functions: cereal third transaminase, aspartate aminotransferase 2.5 x or less UNL (upper limit of normal); creatinine clearance (Cockcroft - Gault method) or 60 mL/min. serum total bilirubin and alkaline phosphatase (1.5 x or less UNL. glomerular filtration rate > 50 mL/min heart ejection fraction (EF) 45% or higher; indoor natural air environment, basic oxygen saturation > 92% blood routine: neutrophils absolute number > 1000 cells/mm3, platelet count 45 x109, 8.0 g/dL hemoglobin; 9. Allowed to have received a previous stem cell transplant 10. Approved anti-B-cell lymphoma therapies, such as systemic chemotherapy, systemic radiotherapy and immunotherapy, had been completed for at least 3 weeks before the study. The eluting period of targeted drug regimens without chemotherapy was 2 weeks; 11. Patients who had previously received CAR T cell therapy and failed to respond to a 3-month evaluation or relapsed were admitted; 12. Female subjects of childbearing age must test negative for pregnancy and agree to use effective contraceptive methods during the trial 13. Two tests have come back negative for COVID-19. Exclusion Criteria: Allergic to any of the components of cell products; History of other tumors; Acute GvHD or generalized chronic GvHD with grade II-IV (Glucksberg standard) after previous allogeneic hematopoietic stem cell transplantation; Or being treated with anti-GVHD; Had received gene therapy in the past 3 months; Active infections requiring treatment (other than simple urinary tract infections and bacterial pharyngitis), however, prophylactic antibiotics, antiviral and antifungal infections are allowed; Subjects infected with hepatitis B (HBsAg positive, but HBV-DNA<103 is not excluded) or hepatitis C virus (including virus carriers), syphilis and other acquired and congenital immunodeficiency diseases, including but not limited to HIV-infected persons; Subjects with Grade III or IV cardiac insufficiency according to the New York Heart Association Cardiac Function Grading criteria; Patients who received antitumor therapy in the early stage but the toxicity reaction did not recover (CTCAE 5.0 toxicity reaction did not recover to ≤ level 1, except fatigue, anorexia and alopecia); Subjects with a history of epilepsy or other central nervous system diseases; Skull enhanced CT or MRI showing evidence of central nervous system lymphoma; Lactating women who refuse to stop breastfeeding; Any other circumstances that the investigator believes may increase the subject's risk or interfere with the test results.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CB dualCAR-NK19/70<br>All subjects were intravenously administrated with CB dualCAR-NK19/70 | Biological: CB dualCAR-NK19/70<br>* Lentiviral vector-transducted cord blood-derived NK cells to express anti-CD19/CD70 CAR and IL15<br>|

What is the study measuring?
-----------------
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 |
| --- | --- | --- |
| Overall survival (OS) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 2 years | 
| Overall response rate (ORR) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 2 years | 
| Duration of response (DOR) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 2 years | 
| Complete response rate (CR) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 2 years | 
| Partial response rate (PR) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 2 years | 
| Progression free survival (PFS) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 2 years |