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

Zhejiang University

Status and phase

Invitation-only

Phase 1

Conditions

Refractory/recurrent Central Nervous System Lymphoma

Treatments

Biological: anti-CD19 CAR-NK cells

Study type

Interventional

Funder types

Other

Identifiers

NCT06827782

ID2024482

Details and patient eligibility

About

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.

Full 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.

Enrollment

42 estimated patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

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.