cord blood-derived car-nk cells targeting cd19 for refractory/relapsed central nervous system lymphoma

Conditions: Refractory/recurrent Central Nervous System Lymphoma

Summary: 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.

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.

Eligibility criteria:
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.

Keywords: refractory or recurrent central nervous system lymphoma diffuse large b cell lymphoma car-nk