CD70-CAR-NK Cell Therapy for T Cell Lymphoma and Acute Myeloid Leukemia

Despite significant advances in CAR-T cell therapy for refractory and relapsed B-cell malignancies and multiple myeloma, CAR-T therapy for T cell lymphoma and acute myeloid leukemia only resulted in suboptimal response partly due to the lack of an ideal target and possible fratricide. Chimeric antigen receptor (CAR)-NK cells may have advantages over CAR-T cells, such as reducing cytokine release and preventing fratricide and tumor contamination in T-cell lymphoma. CD70, which is overexpressed in tumor cells in T cell lymphoma and AML but minimally in normal tissues or hematopoietic stem cells, has emerged as a novel immunotherapy target. Inhibition of the growth of CD70-positive tumors through blocking the CD70/CD27 pathway potentially led to clinical response in relapsed/refractory T-cell lymphoma and AML.

In preclinical studies, we and others have shown that CD70 CAR-NK cells effectively suppress the growth of lymphoma and AML xenograft in vivo, extending the survival of tumor-bearing mice but without significant toxicities. This study aims to evaluate the safety, pharmacokinetics, and efficacy of CD70-targeted CAR-NK cells in patients with CD70-positive relapsed/refractory T-cell lymphoma and AML.

Inclusion criteria

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

• Voluntarily participate in this study and sign the informed consent form;
• Aged between 18-75 years old, both male and female are eligible;
• 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;
• The expected survival period ≥ 12 weeks;
• 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);
• ECOG score is 0 - 2;
• 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);
• Previous autologous hematopoietic stem cell transplantation is allowed once;
• Patients who have previously received CAR - T cell therapy and were evaluated as ineffective after 3 months or relapsed after CR are allowed;
• Female subjects of childbearing age must have a negative pregnancy test and agree to take effective contraceptive measures during the trial period;
• No active lung infection, and indoor air blood oxygen saturation ≥ 92%;
• 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;
• 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:

• Those with a history of allergy to any component in the cellular product;
• Those with a history of other tumors;
• 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;
• Those who have received gene therapy within the past 3 months;
• Those with active infections requiring treatment (except for simple urinary tract infections and bacterial pharyngitis). However, prophylactic antibiotic, antiviral, and antifungal treatments are permitted;
• 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;
• Subjects with grade III or IV cardiac insufficiency according to the New York Heart Association cardiac function classification standard of the United States;
• 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);
• Subjects with a history of epilepsy or other central nervous system diseases;
• Lactating women who are unwilling to stop breastfeeding;
• Any other circumstances that, in the opinion of the investigator, may increase the risk to the subject or interfere with the test results;
• Those with positive nucleic acid tests for COVID - 19 or influenza A.