CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

According to the WHO disease classification, patients with relapsed/refractory T - lymphoma and acute myeloid leukemia:

1. Voluntarily participate in this study and sign the informed consent form;
2. Aged between 18-75 years old, both male and female are eligible;
3. Relapsed/refractory T cell lymphoma is defined as: relapsed/refractory after having received at least two or more lines of previous treatment (patients with anaplastic large -cell lymphoma must have been exposed and resistant to Brentuximab vedotin). The celluar subtypes of T-cell lymphoma include: angioimmunoblastic T-cell lymphoma; peripheral T - cell lymphoma not otherwise specified; ALK-negative anaplastic large - cell lymphoma; Relapsed/refractory AML is defined as: leukemia cells reappear in the peripheral blood after complete remission or the blasts in the bone marrow ≥ 5% or the extramedullary leukemia infiltration outside. Or newly diagnosed cases did not achieve a CR after two courses of standard regimens; those who relapse within 12 months after CR after consolidation and intensification treatment; those who relapse after 12 months and have not responded to conventional chemotherapy; those who relapse two or more times; those with persistent extramedullary leukemia;
4. The expected survival period ≥ 12 weeks;
5. CD70 expression is positive in tumor tissue puncture sections/tumor cells detected by flow cytometry, and the number of CD70 - positive cells detected by immunohistochemistry ≥ 20% (++ or more);
6. ECOG score is 0 - 2;
7. Adequate organ function reserve:

   * Alanine aminotransferase and aspartate aminotransferase ≤ 2.5× UNL;
   * Creatinine clearance rate (Cockcroft - Gault method) ≥ 60 mL/min;
   * Serum total bilirubin and alkaline phosphatase ≤ 1.5× UNL;
   * Glomerular filtration rate \> 50 ml/min;
   * Cardiac ejection fraction ≥ 45%;
   * Under indoor natural air environment, the basic oxygen saturation \> 92%;
   * Routine blood test: absolute neutrophil count \> 1000/mm3, platelet count ≥ 45×109, hemoglobin ≥ 8.0g/dl (the standard for AML patients is ≥ 7.0g/dl; blood transfusion is allowed);
8. Previous autologous hematopoietic stem cell transplantation is allowed once;
9. Patients who have previously received CAR - T cell therapy and were evaluated as ineffective after 3 months or relapsed after CR are allowed;
10. Female subjects of childbearing age must have a negative pregnancy test and agree to take effective contraceptive measures during the trial period;
11. No active lung infection, and indoor air blood oxygen saturation ≥ 92%;
12. Before the study drug is used, approved anti - tumor treatment methods, such as systemic chemotherapy, whole - body radiotherapy, and immunotherapy, have been completed for at least 3 weeks; the wash - out period for targeted drug regimens without chemotherapy is 2 weeks;
13. Two negative tests for COVID - 19 or influenza A.

Exclusion Criteria:

Subjects meeting any of the following criteria will not be eligible for this study:

1. Those with a history of allergy to any component in the cellular product;
2. Those with a history of other tumors;
3. Those who had grade II - IV (Glucksberg criteria) acute GvHD or extensive chronic GvHD after previous allogeneic hematopoietic stem cell transplantation; or those who are currently receiving anti - GvHD treatment;
4. Those who have received gene therapy within the past 3 months;
5. Those with active infections requiring treatment (except for simple urinary tract infections and bacterial pharyngitis). However, prophylactic antibiotic, antiviral, and antifungal treatments are permitted;
6. Subjects with hepatitis B (HBsAg - positive, but HBV - DNA \< 103 is not an exclusion criterion) or hepatitis C virus infection (including virus carriers), syphilis, and other acquired or congenital immunodeficiency diseases, including but not limited to those infected with the AIDS virus;
7. Subjects with grade III or IV cardiac insufficiency according to the New York Heart Association cardiac function classification standard of the United States;
8. Those whose toxic reactions from previous anti - tumor treatment have not recovered (CTCAE 5.0 toxic reactions have not recovered to ≤ grade 1, except for fatigue, anorexia, and alopecia);
9. Subjects with a history of epilepsy or other central nervous system diseases;
10. Lactating women who are unwilling to stop breastfeeding;
11. Any other circumstances that, in the opinion of the investigator, may increase the risk to the subject or interfere with the test results;
12. Those with positive nucleic acid tests for COVID - 19 or influenza A.

主要终点：The incidence and type of dose-limiting toxicity (DLT) within 28 days · To determine the incidence and type of dose-limiting toxicity (DLT) within 28 days after CD70-CAR - NK cell infusion · 28 days；the incidence and severity of treatment-related adverse events as assessed by CTCAE v4.0 · CAR-NK treatment-related AEs include CRS, ICANS, cytopenia, and other non-hematological toxicities · within 90 days after CAR-NK infusion
次要终点：Objective response rate (ORR) at day 30；duration of response；progression-free survival

• CD70 CAR-NK for the treatment of CD70-positive relapsed/refractory T-cell lymphoma and AML · EXPERIMENTAL · The first stage is a dose escalation study, with three CD70 CAR-NK dose levels. Each dose level is planned to recruit 3 to 6 subjects to evaluate safety and efficacy and determine the number of CD70 CAR-NK cells for treatment in the second stage. The second stage is the dose expansion stage, where 30 subjects are recruited to receive the number of CD70 CAR-NK cells recommended in the first stage.

CD70 is a promising target for immunotherapy because it is overexpressed in T-cell lymphoma (TCL) and acute myeloid leukemia (AML) tumor cells but is found in deficient levels in normal tissues and hematopoietic stem cells. This study aims to evaluate the safety and efficacy of CD70-targeted CAR-NK (CD70-CAR-NK) cells in patients with relapsed and refractory TCL and AML.