study of cord blood-derived car nk cells targeting cd19/cd70 in refractory/relapsed b-cell non-hodgkin lymphoma

Conditions: Refractory or Relapsed B-cell Non-Hodgkin Lymphoma

Summary: to find the highest tolerable dose of dualcar-nk19/70 (a type of cell therapy) that can be given to patients who have b-cell lymphoma that is relapsed or refractory.

primary objectives: --the primary objective is to determine the safety and identify the maximum tolerated dose (mtd) or recommended phase 2 dose (rp2d) of dualcar-nk19/70 in patients with r/r b-cell lymphomas. hypothesis: dualcar-nk19/70 will be safe, well-tolerated, and effective in patients with r/r b-cell lymphomas. secondary objectives: --the secondary objective is to determine the efficacy in adults with r/r lbcl and fl grade 3b treated at the mtd or rp2d of dualcar-nk19/70. although the clinical benefit of dualcar-nk19/70 has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. secondary endpoints include overall response rate (orr; including cr + pr) and cr rate as defined by the lugano classification response criteria for malignant lymphoma, dor, pfs, and os. exploratory objectives: --the exploratory objectives are to assess the cellular kinetics and pharmacodynamic effects of dualcar-nk19/70 and to evaluate biomarkers associated with response, resistance, and toxicity after administration of dualcar-nk19/70 in blood and tumor samples.

Eligibility criteria:
inclusion criteria: 1. voluntarily participate in the study and sign the informed consent; 2. age 18-75, male and female; 3. histologically confirmed diffuse large b-cell lymphoma (dlbcl), transformed follicular lymphoma (tfl), primary mediastinal b-cell lymphoma (pmbcl), mantle cell lymphoma (mcl), and other indolent b-cell nhl transforming types: （a） relapsed or refractory dlbcl and tfl after 2 lines immunotherapy or chemotherapy ; （b） definition of refractory large b cell lymphoma (scholar - 1 research standard) : disease progression after more than 4 courses of standard immunotherapy or chemotherapy; or the time of disease stabilization ≤ 6 months; or disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation (auto-hsct); （c） relapsed or refractory mcl must be 1 line with immune chemotherapy; btk inhibitors are resistant or intolerant as 2-line therapy; （d） relapsed or refractory disease after chemotherapy including rituximab and anthracycline. 4. there was at least one measurable lesion with the longest diameter ≥ 1.5cm; 5. estimated life expectancy of more than 12 weeks other than primary disease; 6. previously confirmed diagnosis as cd19+ or cd70+ b-nhl. 7. eastern cooperative oncology group (ecog) performance status of 0 - 3. 8. adequate reserve of organ function: （a） serum alanine aminotransferase (alt) / aspartate aminotransferase (ast) ≤2.5 times the upper limit of normal (uln) for age; （b） a creatinine clearance (as estimated either by a direct urine collection or cockcroft-gault equation) \> 60ml/min; （c） total bilirubin and alkaline phosphatase ≤1.5 times the upper limit of normal (uln) for age; （d） glomerular filtration rate \> 50 ml/min （e） cardiac ejection fraction (ef) ≥ 45% as determined by an echocardiogram (echo) or multigated radionuclide angiography (muga); （f） baseline oxygen saturation \>92% on room air （g） absolute neutrophil count \> 1000/μl, platelet count \> 45,000/μl ,hemoglobin \> 80g/l; 9. once previous autologous hematopoietic stem cell transplantation (auto-hsct) is allowed; 10. for systemic therapy(such as systemic chemotherapy, systemic radiotherapy and immunotherapy), at least 3 weeks，for targeted drug therapy alone，at least 2 weeks，must have elapsed at the time of cell infusion; 11. either having failed or relapsed after car-t therapy at 3 months of assessment; 12. subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study. women of childbearing potential must have a negative serum or urine pregnancy test. 13. the viral load of severe coronavirus disease 2019 (covid-19) is undetectable per quantitative pcr and/or nucleic acid testing for two tests. exclusion criteria: 1. allergic to any of the components of cell products; 2. previous or concurrent of other type of maligant tumors; 3. acute gvhd or generalized chronic gvhd with grade ii-iv (glucksberg standard) after previous autologous hematopoietic stem cell transplantation (auto-hsct); or receiving of anti-gvhd therapy; 4. known history of systemic gene therapy within the prior 3 months; 5. active systemic fungal, viral, or bacterial infection (except for simple urinary tract infections and bacterial pharyngitis), however, preventive treatment is permitted; 6. known history of infection with hepatitis b (hbsag positive, but hbv-dna\<1000 is not excluded) or hepatitis c virus (including virus carriers), syphilis and other acquired and congenital immunodeficiency diseases, including but not limited to hiv infection; 7. class iii or iv heart failure as defined by the new york heart association; 8. persisting toxicities (\>grade 1, except for clinically non-significant toxicities such as alopecia, fatigue, and anorexia) due to prior trerapy; 9. known history of active seizures or presence of seizure activities or other central nervous system disease; 10. have evidence of central nervous system lymphoma(cns lymphoma) on ct or mri; 11. breast-feeding woman; 12. any circumstances that possibly increase the risk of subjects or interfere with study results, which judged by investigator.

Keywords: b-cell non-hodgkin lymphoma car nk cells targeting cd19/cd70 cord blood-derived