Extranodal NK T Cell Lymphoma, NK-Cell Leukemia
Conditions
Keywords
Anti-CD56 CAR-T
Brief summary
To evaluate the safety and efficacy of anti-CD56-CAR T in the treatment of relapsed refractory NK/T cell lymphoma /NK cell leukemia
Detailed description
Extranodal NK/TCL is an aggressive disease with a poor prognosis and a 5-year survival rate of less than 50%. In the absence of effective treatment, median survival for advanced disease is only 6-12 months. A retrospective review of the International Peripheral T-Cell Lymphoma Project recently reported that the median overall survival of NK/TCL was 7.8 months, corresponding to the worst survival of all T-cell lymphoma entities. Therefore, despite good results in the combination of chemoracal-chemotherapy strategies, autologous bone marrow transplantation, and L-asparagase in the treatment of recurrent cases, NK/TCL remains difficult to cure, and the need for alternative therapeutic strategies has prompted researchers to explore new molecular targets. Nerve cell adhesion molecule 1 (NCAM-1) -CD56 is a member of the immunoglobulin superfamily and is a biomarker of nerve cell adhesion molecule and NK cell. CD56 is highly expressed in NK/T cell lymphomas, skeletal muscle tumors, and malignancies with neurological or neuroendocrine differentiation. CD56-CAR T cells can kill CD56+ neuroblastoma, glioma, and SCLC tumor cells in vitro coculture, and CD56R-CAR+T cells can inhibit tumor growth in vivo when tested against CD56+ human neuroblastoma xenogeneic and SCLC models. CD56-CAR T cells have also been reported as a safe and effective treatment for refractory/relapsing rhabdomyosarcoma. This indicates that CD56 CAR has a wide clinical application prospect and strong potential therapeutic value as a new CAR T target. CD56 CAR T cells constructed by our laboratory can produce more precise killing effect on tumor cells by converting the immune checkpoint PD-1 signal. The results showed that CD56 CAR T cells could be prepared effectively and kill NK/ T-cell lymphoma cell line SNK-6 in vitro. Compared with traditional second-generation CAR T cells, CD56-CAR T cells prepared in our laboratory showed better killing effect on SNK-6 cells in vitro. At present, no clinical studies on CD56 CAR T therapy for NK/T cell lymphoma have been reported. Therefore, in this study, CD56 CAR T was used to treat relapsed and refractory NK/T cell lymphoma /NK cell leukemia to observe its safety and efficacy.
Interventions
BIOLOGICALAnti-CD56 CAR T
CAR T cells were pretreated at -5 days before retransfusion (FC regimen: fludarabine: 30mg/m2×3 days, cyclophosphamide: 750mg/m2×1 day). Anti CD56-CAR T cells were transfused back to the patient 2 days after the end of chemotherapy. 30 to 60 minutes before CAR T cell infusion, patients were given 325 to 650 mg of acetaminophen orally to prevent infusion-related reactions; If fever occurred on the day of CAR T cell infusion, lasted less than 24 hours, and had no other toxicity, it was attributed to the infusion T cell response.
Sponsors
The Affiliated Hospital of Xuzhou Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients or their legal guardians voluntarily participate and sign the informed consent; 2. Male or female patients aged 18-70 years (including 18 and 70 years); 3. The patient was diagnosed as NK/T cell lymphoma /NK cell leukemia by pathology or flow cytometry, and currently has no effective treatment options, such as relapse after chemotherapy or hematopoietic stem cell transplantation; Alternatively, patients voluntarily choose to administer anti-CD56-CAR T cells as salvage therapy. 4. The following two categories are included:(1)NK/T cell lymphoma;(2) NK cell leukemia. 5. Subject: (1)There was no remission or residual lesions after treatment, and HSCT (auto/allo-HSCT) was not suitable; (2)Relapse occurred after CR, and HSCT (auto/allo-HSCT) was not suitable; (3)Patients with high risk factors; (4)Relapse or no remission after hematopoietic stem cell transplantation or cellular immunotherapy. 6\. Measurable or evaluable lesions; 7\. The patient's main tissues and organs function well: 1. Liver function: ALT/AST \< 3 times the upper limit of normal (ULN) and total bilirubin ≤34.2μmol/L; 2. Renal function: creatinine \< 220 μmol/L; 3. Lung function: indoor oxygen saturation ≥95%; 4. Cardiac function: left ventricular ejection fraction (LVEF) ≥40%. 8\. The patients had not received any anti-cancer treatment such as chemotherapy, radiotherapy, immunotherapy (such as immunosuppressive drugs) within the first 4 weeks of enrollment, and their previous treatment-related toxic reactions had recovered to ≤ grade 1 at the time of enrollment (except low toxicity such as hair loss); 9\. The patient's peripheral shallow venous blood flow is smooth, which can meet the needs of intravenous infusion; 10\. Patients with ECOG score ≤2 and expected survival time ≥3 months.
Exclusion criteria
1. Women who are pregnant (urine/blood pregnancy test positive) or breastfeeding; 2. Men or women who have planned to become pregnant within the last 1 year; 3. The patients were not guaranteed to take effective contraceptive measures (condoms or contraceptives, etc.) within 1 year after enrollment; 4. Patients had uncontrollable infectious diseases within 4 weeks prior to enrollment; 5. Active hepatitis B/C virus; 6. HIV-infected patients; 7. Suffering from a serious autoimmune disease or immunodeficiency disease; 8. The patient is allergic to antibodies, cytokines and other macromolecular biological drugs; 9. The patient had participated in other clinical trials within 6 weeks prior to enrollment; 10. Systemic use of hormones within 4 weeks prior to enrollment (except for inhaled hormones); 11. Suffers from mental illness; 12. The patient has substance abuse/addiction; 13. According to the researchers' judgment, the patient had other conditions that were not suitable for inclusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | From 1 month to 1 year. | CR+PR.1.Leukemia:Complete Response (CR):Bone marrow blast cells \<5%; primitive cells without Auer bodies; without extramedullary leukemia;Absolute blood neutrophil count was\> 1.0\*10\^9 / L (1000 / μ L);Platelet count\> 100\*10\^9 / L (100 000 / μ L);Not dependent on RBC infusion.Partial Response (PR):Only for Phase I and II clinical trials;Bone marrow cells were reduced to 5 - 25% and at least 50% compared with before treatment;Hematological parameters met the same criteria for CR. 2.Lymphoma:CR:All the evidence of the lesions disappeared.PR:The lymph nodes shrank with no new lesions. |
| progression-free survival (PFS) | From 1 month to 1 year. | The time between treatment and observation of disease progression or death from any cause. |
| overall survival (OS) | From 1 month to 1 year. | The time from the start of treatment to death from any cause. |
| event-free survival (EFS) | From 1 month to 1 year. | The time between the start of treatment and the occurrence of any event, including disease recurrence, death, and so on. |
| Safety evaluation index | From 1 month to 1 year. | 1\. Detection of CRS-related factors: such as IFN, IL-6, TNF, IL-10, IL-4, CRP, etc;2. Testing of various laboratory items: blood routine, coagulation function, blood film observation, liver function, renal work, electrolytes, blood glucose, cardiac enzymes, blood cells, T cell subsets, immunoglobulins, etc;3.Adverse events and serious adverse events were observed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CAR T cell index of correlation | From 1 month to 1 year. | The presence of peripheral blood and bone marrow CAR-T cells were measured regularly by using flow cytometry, quantitative PCR techniques. |
Countries
China
Outcome results
None listed