CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Patients who met all the inclusion criteria were eligible for enrolment.

  1. Patients diagnosed with primary resistance acute myeloid leukemia, tumour surface antigen CD33 expression, chemotherapy relapse, extramedullary relapse, persistent residual positivity or relapse/refractory after allogeneic haematopoietic stem cell transplantation;
  2. Age 1-70 years old;
  3. No severe allergies;
  4. Physical condition: 0-2 ECOG score;
  5. Expected survival ≥ 60 days;
  6. Bone marrow or cerebrospinal fluid tumour cells are positive for CD33 by flow cytometry assay or tumour tissues positive for CD33 by immunohistochemistry (CD33 determination of positivity: flow cytometry: \>80% of tumour cells expressing CD33 and MFI similar to normal myeloid cells is considered as full positivity; tumour cells greater than 80% of expression of CD33 but MFI lower than the CD33 expression of normal myeloid cells by 1 log is considered as low expression (dim). Tumour cells with between 20-80% positive CD33 expression are partially expressed; Pathological immunohistochemistry: tumour cells\>30% positive are considered to be positively expressed;
  7. Self-aware patients aged 19-70 years are required to voluntarily sign an informed consent form in writing; paediatric patients aged 1-7 years can be recruited after their legal representative (guardian) had signed an informed consent form; self-aware paediatric patients aged 8-18 years voluntarily sign an informed consent form in writing, and their legal representative (guardian) are required to sign an informed consent form in writing as well;
  8. Suitable and available allogeneic haematopoietic stem cell transplant donors are required, and allogeneic haematopoietic stem cell transplantation can be performed after receiving FL-33 CAR T treatment.

Exclusion Criteria:

* Patients who fulfil any of the following criteria may not be enrolled.

  1. Patients with history of allogeneic HSCT but PBMNC is not available from prior- transplant donor for preparation of CAR T cells and peripheral blood tumour load \>30%; patients without history of allogeneic HSCT and peripheral blood tumour load \>30%;
  2. Intracranial hypertension or cerebral impaired consciousness;
  3. Symptomatic heart failure or severe arrhythmia;
  4. Symptoms of severe respiratory failure;
  5. With other types of malignancy;
  6. Diffuse intravascular coagulation;
  7. Serum creatinine and/or urea nitrogen ≥ 1.5 times the normal value;
  8. With sepsis or other uncontrollable infection;
  9. Suffering from uncontrollable diabetes mellitus;
  10. Severe mental disorders;
  11. Have significant intracranial lesions on cranial MRI;
  12. Organ transplantation (excluding haematopoietic stem cell transplantation) history;
  13. Female patients (patients of childbearing potential) with positive blood HCG test;
  14. Hepatitis (including hepatitis B and C) and positive screening for AIDS and syphilis.

主要终点：Dose-limiting toxicity(DLT) · Incidence and type of dose-limiting toxicity(DLT) within 21 days of FL-33 CAR T infusion. · 21 days；Adverse events (AEs) · Total number, incidence and severity of adverse events (AEs) within 30 days of FL-33 CAR T infusion. · 30 days
次要终点：Long-term Adverse events (AEs)；Objective Response Rate (ORR)；Duration of response (DOR)；Progression-free survival (PFS)；Overall survival (OS)；The persistence of FL-33 CAR T cells

• Autologous FL-33 CAR T · EXPERIMENTAL · Peripheral blood mononuclear cells for the production of FL-33 CAR T cells are collected from patients.
• Prior-HSCT donor-derived FL-33 CAR T · EXPERIMENTAL · Peripheral blood mononuclear cells for the production of FL-33 CAR T cells are collected from prior-HSCT donors.
• Newly matched donor-derived FL33 CAR T · EXPERIMENTAL · Peripheral blood mononuclear cells for the production of FL-33 CAR T cells are collected from newly matched donors.
• FL-33-03 CAR T · EXPERIMENTAL · The independent observation group, serving as an exploratory arm, will uniformly enroll at least 3 subjects starting from the lowest dose level (DL-1) into Cohort 1 to evaluate the safety and efficacy of FL33-03 CAR-T (with TNFα inhibitor). If the results from this stage meet expectations, at least 3 additional subjects will be enrolled into Cohort 2 to evaluate the safety and efficacy of FL33-03 CAR-T (without TNFα inhibitor) at the same lowest dose level.

This study is a multi-center, open-label, non-randomised, single-arm phaseⅠclinical trial to explore the safety and efficacy of FL-33 CAR T therapy for refractory/relapsed acute myeloid leukaemia. The primary endpoints are incidence and type of dose limiting toxicity within 21 days of CAR T infusion; total number, incidence and severity of adverse events (AE) 30 days after CAR T infusion. The secondary endpoints are total number, incidence and severity of AEs 30 days to 2 years after CAR T infusion; objective response rate (ORR), complete response rate (CR) and complete response with incomplete haematological recovery (CRi) by dose group at 15, 30 and 90 Days after CAR T Infusion; duration of response (DOR), progression-free survival (PFS), overall survival (OS); pharmacokinetic characteristics. The trial will use BOIN12 design to explore the optimal biological dose (OBD) of FL-33 CAR T cells for refractory/relapsed acute myeloid leukaemia. FL-33 CAR T is set at two dose levels: 5\*10\^5 (±20%) CAR-T cells/kg for dose 1 (DL-1) and 1\*10\^6 (±20%) CAR-T cells/kg for dose 2 (DL-2), and after the optimal biological dose (OBD) is determined in the dose exploration phase, the dose expansion phase will expand the trial by 6-12 cases at the OBD, enrolling up to 21-27 cases. Enrolment of more than 21 cases can be reported for analysis and the trial will be stopped when enrolment reaches 27 cases.Additionally, an independent observation group was established, comprising two sequential cohorts: a minimum of 3 subjects were enrolled starting from the lowest dose level (DL-1).