LILRB4 STAR-T Cells in the Treatment of R/R AML/CMML

This study is an exploratory study to evaluate the safety, tolerability, and efficacy of LILRB4 STAR-T cells in relapsed and refractory acute myeloid leukemia/Chronic Granulocytic-Mononocytic Leukemia subjects.

This study will recruit LILRB4 positive AML/Chronic Granulocytic-Mononocytic Leukemia subjects,and Subjects will receive cytoreductive chemotherapy with cyclophosphamide and fludarabine on days -5, -4 and -3 followed by infusion of LILRB4 STAR-T cells. LILRB4 STAR-T cells will be intravenously infused with a escalated dose of 1E6, 3E6, 6E6, 1E7 cells/kg.Safety and efficacy of LILRB4 STAR-T cells therapy will be monitored.The primary endpoint of the study is to observe DLT, AE, SAE, CRS and ICANS. Secondary objectives are to observe the efficacy of LILRB4 STAR-T cells, including Disease response, CR rate, ORR, RFS, EFS, OS, PK, PD and ADA.

Eligibility Criteria:
Inclusion Criteria:

(A) Subjects must meet all of the following enrollment criteria to be enrolled in this study.

1. Age ≥ 18 years,≤ 60 years and gender;
2. Patients with acute myeloid leukemia or chronic granulomonocytic leukemia; 1) Patients with acute myeloid leukemia (AML) diagnosed according to the World Health Organization (WHO) 2016 criteria and who should meet any of the following relapsed-refractory (R/R) AML according to the Chinese Guidelines for the Diagnosis and Treatment of Relapsed-Refractory Acute Myeloid Leukemia (2021 Edition):

   * Primary patients who have failed 2 courses of treatment with a standard regimen (containing cytarabine and an anthracycline or anthraquinone);
   * Those who relapsed within 12 months after complete remission (CR) with consolidation and intensive therapy;
   * Those who relapsed after 12 months but failed to respond to conventional treatment;
   * Those with 2 or more recurrences;
   * Those with persistent extramedullary leukemia. Note: Definition of relapse: reappearance of leukemic cells in the peripheral blood or \>5% of primitive cells in the bone marrow after CR (except for other reasons such as bone marrow regeneration after consolidation chemotherapy) or extraparenchymal infiltration of leukemic cells.

     2) Chronic granulocytic-monocytic leukemia diagnosed according to the World Health Organization (WHO) 2016 Classification Criteria for Tumors of Hematopoietic and Lymphoid Tissues and the Chinese Guidelines for the Diagnosis and Treatment of Chronic Granulocytic-Mononocytic Leukemia (2021 edition), with relapse refractory defined as follows: at least 2 complete cycles of at least one treatment (e.g., demethylating drugs ) or allogeneic hematopoietic stem cell transplantation (allo-HSCT) ) without achieving remission or relapse after remission.
3. ECOG score 0-2;
4. Bone marrow samples were positive for LILRB4 (flow-through assay);
5. Good organ function:

   Liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine transaminase (AST), alanine transaminase (ALT) ≤ 3 x ULN; Renal function: serum creatinine (Cr) ≤ 1.5 x ULN or creatinine clearance (Cockcroft-Gault formula) ≥ 60 mL/min; Cardiac function: left ventricular ejection fraction (LVEF) ≥50%; Pulmonary function: defined as ≤ grade 1 dyspnea and oxygen saturation \> 92%.
6. Female subjects of childbearing age or male subjects whose partner is a woman of childbearing age agree to use an effective method of contraception throughout the trial and for 12 months after cell infusion;
7. Subjects voluntarily enrolled in the study, signed an informed consent form, were compliant, and cooperated with follow-up visits.

(B) The provider must fulfill the following conditions:

1. Age greater than or equal to 12 years;
2. HLA mating types are at least hemi-compatible;
3. Adequate venous access is available for peripheral blood leukocyte isolation;
4. Voluntary written informed consent.

Exclusion criteria

(A) Subjects who meet any of the following criteria are not eligible for enrollment in this study

1. Patients who have used CAR-T cell therapy or any other therapeutic product such as gene transduction within 3 months of signing the informed consent, except for those with undetectable CAR-T or CAR-T below the lower limit of detection; or patients who have participated in an interventional clinical study of an antitumor drug within 4 weeks prior to signing the informed consent;
2. Individuals with a history of any of the following cardiovascular diseases within 6 months prior to screening: (1) congestive heart failure (New York Heart Association \[NYHA\] class ≥III), myocardial infarction, unstable angina, congenital long QT syndrome, left anterior hemiblock (bifascicular block), coronary angioplasty, stenting, coronary/peripheral artery bypass grafting, cerebrovascular accident ( CVA), transient ischemic attack, or pulmonary embolism, allowing for asymptomatic right bundle branch block; (2) severe cardiac arrhythmias requiring treatment (e.g., sustained ventricular tachycardia, ventricular fibrillation, tip-twist ventricular tachycardia, etc.); and (3) suffering from uncontrolled hypertension (systolic blood pressure greater than 160 mmHg and/or diastolic blood pressure greater than 100 mmHg), a history of hypertensive crisis, or hypertensive encephalopathy;
3. Hepatitis B surface antigen (HBsAg) positive, Hepatitis B core antibody (HBcAb) positive subjects with peripheral blood HBV DNA copy number higher than the limit of detection, Hepatitis C virus (HCV) antibody positive subjects with HCV RNA copy number higher than the limit of detection, and Syphilis spirochete antibody test positive subjects;
4. Patients with known systemic lupus erythematosus, comorbid active or uncontrolled autoimmune diseases (e.g., Crohns disease, rheumatoid arthritis, autoimmune hemolytic anemia, etc.), and primary or secondary immunodeficiencies (e.g., HIV infection or severe infectious diseases, etc.);
5. Pre-existing or concurrent other untreated malignancies of indolent control affecting the subject's long-term survival, except cured carcinoma in situ of the uterine cervix, non-invasive basal cell or squamous cell skin cancers, or other malignancies that have been radically treated with localized prostate cancer, or ductal carcinoma in situ after radical surgery, and that have remained free of recurrence for at least 5 years;
6. Patients with current or previous history of CNS disorders such as seizures, stroke, severe brain injury aphasia, paralysis, dementia, Parkinson's disease, psychiatric disorders;
7. Those with active central nervous system leukemia (CNSL) present at screening;
8. History of solid organ transplantation or hematopoietic stem cell transplantation (HSCT) within 6 months prior to screening;
9. Those with acute or chronic graft-versus-host disease (GVHD) at screening;
10. Use of patients who have had any of the following medications or treatments performed within the designated time period prior to single-take:

    * Have used any immunosuppressant within 2 weeks prior to single harvesting;
    * Received any chemotherapy or small molecule targeted therapy within 2 weeks or 3 half-lives (whichever is shorter) prior to monoacquisition;
    * Received any large molecule therapy such as monoclonal antibody, antibody coupled drug (ADC), or doublet within 4 weeks or 3 half-lives (whichever is shorter) prior to monoacquisition;
11. People with mental illness, or a history of substance abuse;
12. Pregnant or lactating subjects;
13. Other factors that, in the opinion of the investigator, make enrollment inappropriate or affect the subject's participation in or completion of the study.

(B) Donor exclusion criteria

Any of the following points are used as provider/third party exclusion criteria:

1. A history of mental disorder that may interfere with compliance with the program or prevent signing the informed consent form;
2. History of uncontrollable high blood pressure with medication, stroke or severe heart disease;
3. There is anemia or thrombocytopenia;
4. HBsAg-positive, or HBcAb-positive and peripheral blood HBV DNA-positive; HCV-antibody-positive individuals and HCV RNA-positive; syphilis spirochete antibody-positive; HIV antibody-positive;
5. Presence or suspicion of uncontrolled fungal, bacterial, viral or other infections;
6. Pregnancy;
7. Any other circumstances that the investigator deems inappropriate as a donor/third party.