Cord Blood-derived CAR-NK Cells Targeting CD19 for Refractory/Relapsed Central Nervous System Lymphoma

Clinical Study of Cord Blood-derived CAR-NK Cells Targeting CD19 in the Treatment of Refractory/Relapsed Central Nervous System Lymphoma

This study is designed to evaluate the safety and efficacy of cord blood-derived CAR-NK019 in the treatment of refractory/relapsed central nervous system lymphoma.

Study Overview

• Status: Enrolling by invitation
• Conditions: Refractory/Recurrent Central Nervous System Lymphoma
• Intervention / Treatment: Biological: anti-CD19 CAR-NK cells

Detailed Description

This study is a single-center, open, single-arm incremental, exploratory study designed to evaluate the safety and efficacy of cord blood-derived CAR-NK019 in the treatment of refractory/relapsed central nervous system lymphoma.

The study will be divided into two stages: Phase I is the dose escalation study, which is strictly based on the "3+3" dose escalation principle, and three dose groups are set up, which are administered through the ommaya capsule ventricle, and each dose is infused once a week for 3 weeks. Three to six subjects are intended to be enrolled in each dose group, with each subject observed for at least 28 days after receiving the initial infusion and a long-term follow-up period of two years after each infusion. Phase II is the dose expansion phase: The recommended dose and administration mode for this phase will be determined after comprehensive consideration based on safety data obtained in phase I, the proliferation and survival of CAR-NK cells in vivo, and clinical efficacy data, and 24 effective subjects will be recruited for further evaluation of efficacy and safety. Long-term follow-up lasted up to 2 years after the first CAR-NK transfusion in each patient.

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • 2nd Affiliated Hospital, School of Medicine, Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with refractory/recurrent CNS lymphoma must meet all of the following criteria to be eligible:

  1. Voluntarily participate in the study and sign the informed consent;
  2. Age 18-75 years old, male or female;
  3. Diffuse large B-cell lymphoma (DLBCL) was confirmed by histology. CD19 expression was positive by lymphoma pathology or flow cytometry, and CD19 expression was ≥20% by IHC.
  4. Imaging showed no evidence of systemic lymphoma;
  5. Meets any of the following definitions for refractory/relapsed CNS lymphoma: no complete response has been achieved with prior 2-line regimen including methotrexate or cytarabine-based regimen; Disease progression during any treatment; The stable time of disease after effective treatment is less than 6 months; Disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation.
  6. Imaging showed the presence of at least one measurable lesion, with a minimum diameter of ≥10mm;
  7. Expected survival ≥3 months;
  8. ECOG score 0-3 points;

  9. Adequate organ function reserve:

     • alanine aminotransferase, ASpartate aminotransferase ≤ 2.5× UNL (upper limit of normal);
     • Creatinine clearance (Cockcroft-Gault method) ≥60 mL/min;
     • Serum total bilirubin and alkaline phosphatase ≤1.5× UNL;
     • Glomerular filtration rate >50ml/min
     • cardiac ejection fraction (EF) ≥45%;
     • Basic oxygen saturation >92% in indoor natural air environment;
     • Blood routine: absolute number of neutrophils >×109/L, platelet count 45×109/L, hemoglobin 80g/L;
  10. Previous autologous hematopoietic stem cell transplantation is allowed, and the interval between stem cell transfusion and CAR-NK transfusion is ≥3 months;
  11. Previous CAR-T cell therapy is allowed, and the time interval between CAR-T transfusion and CAR-NK transfusion is ≥3 months;
  12. Female subjects of childbearing age must test negative for pregnancy and agree to use effective contraception during the test;
  13. Approved anti-tumor therapies, such as systemic chemotherapy, whole body radiotherapy and immunotherapy, have been discontinued for at least 3 weeks before the study; Discontinuation of targeted drug regiments without chemotherapy for at least 2 weeks;

Exclusion Criteria:

• Subjects who meet any of the following criteria will not be admitted to the study:

  1. Allergic to any of the components of cell products;
  2. History of other tumors;
  3. Acute grade II-IV (Glucksberg standard) GvHD or generalized chronic GvHD occurred after previous allogeneic hematopoietic stem cell transplantation; Or are receiving anti-GVHD treatment;
  4. Have received gene therapy within the past 3 months;
  5. Active infections requiring treatment (except simple urinary tract infections, bacterial pharyngitis), but prophylactic antibiotic, antiviral and antifungal infection treatment is permitted;
  6. Persons 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;
  7. Subjects with Grade III or IV cardiac dysfunction according to the New York Heart Association's cardiac function grading criteria;
  8. Patients who received antitumor therapy in the early stage but did not recover toxicity (CTCAE 5.0 toxicity did not recover to ≤ grade 1, except fatigue, anorexia, alopecia);
  9. Previous history of epilepsy, autoimmune encephalitis, cerebral infarction or cerebral hemorrhage within 6 months;
  10. Whole-body enhanced CT or PET/CT suggests evidence of systemic lymphoma;
  11. Lactating women who are unwilling to stop breastfeeding;
  12. Any other circumstances that the investigator believes may increase the risk to the subject or interfere with the test results;
  13. Patients requiring more than 10mg of dexamethasone per day for 3 days prior to enrollment;
  14. Patients who cannot tolerate ommaya capsule implantation;
  15. Those who cannot tolerate enhanced magnetic resonance imaging.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CB CAR-NK019	Biological: anti-CD19 CAR-NK cells; lentiviral vector-transducted cord blood-derived NK cells to express anti-CD19 CAR

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 refractory/relapsed central nervous system lymphoma	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Complete response rate (CR)	To determine the anti-tumor effectivity of CB CAR-NK019	3 months
Overall response rate (ORR)	To determine the anti-tumor effectivity of CB CAR-NK019	3 months

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: December 29, 2024
• First Submitted That Met QC Criteria: February 10, 2025
• First Posted (Actual): February 14, 2025

Study Record Updates

• Last Update Posted (Estimated): August 15, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Diffuse large B cell lymphoma; CAR-NK; Refractory or recurrent; central nervous system lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma
• Other Study ID Numbers: ID2024482

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No