CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Only patients who meet all the following criteria can be included in the group:

  1. Patients who were diagnosed as primary refractory or relapsed B-ALL. (Criterion-reference: NCCN, version 2.2023); All the patients matched the diagnostic criteria of ALL according to the NCCN guideline (≥20% bone marrow lymphoblasts on hematopathology review of bone marrow aspirate and biopsy materials, which were confirmed by comprehensive flow cytometric immunophenotyping, minimal residual disease analysis and karyotyping of G-banded metaphase chromosomes). Molecular characterization could be obtained via interphase fluorescence in situ hybridization (FISH) testing, reverse transcriptase polymerase chain reaction (RT-PCR) testing, comprehensive testing by next-generation sequencing (NGS) for gene fusions and pathogenic mutations, etc. Determination of the World Health Organization ALL subtypes and cytogenetic and clinical risk groups were also allowed. B-ALL patients who did not achieve a complete remission after previous therapy (including the various treatment response scenarios shown in Table 1), who did not achieve a complete remission after at least two lines of TKI agents (including the various treatment response scenarios shown in Table 1), or who had ≥1 relapses were defined as having refractory or relapsed disease. Patients who were diagnosed as CD19- and CD22-positive high-risk B-ALL with continuous positive minimal residual disease (MRD) for more than three months after last therapy were also eligible. Patients had positive CD19 and CD22 expression on leukemia blasts by FCM (\>80% CD19 and CD22 positive);
  2. Age from 1 to 70 years old;
  3. No serious allergic constitution;
  4. Eastern Cooperative Oncology Group (ECOG) performance status (Oken et al., 1982) score 0 to 2;
  5. Have life expectancy of at least 60 days based on investigator's judgement;
  6. Voluntary informed consent is signed by self-aware patients aged 8-70 years and by legal representatives (guardians) of pediatric patients under 18 years of age.

Exclusion Criteria:

* Patients with at least one of the following conditions are excluded:

  1. Intracranial hypertension or unconscious;
  2. Acute heart failure or severe arrhythmia;
  3. Acute respiratory failure;
  4. Other types of malignant tumors;
  5. Diffuse intravascular coagulation;
  6. Serum creatinine and/or blood urea nitrogen over 1.5 times the normal value;
  7. Sepsis or other uncontrolled infection;
  8. Uncontrolled diabetes mellitus;
  9. Severe psychological disorder;
  10. Obvious cranial lesions by cranial MRI;
  11. More than 20 leukemic cells/μL in cerebrospinal fluid;
  12. More than 30% leukemic cells in the peripheral blood;
  13. Organ recipients;
  14. Pregnant or breastfeeding;
  15. Active, uncontrolled infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or treponema pallidum (TP).

主要终点：EFS in CD19 CAR and CD22 CAR-T sequential infusion (Sequential CAR group) and CD19 CAR T-cell infusion bridging to HSCT (CAR+HSCT group) · Event-free survival (EFS) of children and adolescent and young adult (AYA) with r/r B-ALL treated with CD19 CAR and CD22 CAR T-cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT. EFS is defined as the time from CD19 CAR T-cell infusion to the earliest relapse, death from any cause, or treatment failure. · 2-year EFS rate
次要终点：ORR in Sequential CAR group and CAR+HSCT group；DOR in Sequential CAR group and CAR+HSCT group；OS in Sequential CAR group and CAR+HSCT group；Adverse events (AEs) in Sequential CAR group and CAR+HSCT group；Levels of CD19 and CD22 CAR-T cells in Sequential CAR group；Levels of CD19 CAR-T cells in CAR+HSCT group；Levels of CD19 and CD22 CAR transgene in Sequential CAR group；Levels of CD19 CAR transgene in CAR+HSCT group

• Arm-1: CD19 CAR T and CD22 CAR T-cell sequential treatments (Sequential CAR) · EXPERIMENTAL
• Arm-2: CD19 CAR T-cell treatment bridging to HSCT (CAR+HSCT) · EXPERIMENTAL

This is a multi-center, open-label, non-randomized, two-arm, non-inferior trial. Patients with r/r B-ALL would be assigned to the CD19 CAR and CD22 CAR T-cell sequential infusion group (Sequential CAR, Arm-1) and the CD19 CAR T-cell infusion bridging to hematopoietic stem cell transplantation group (CAR+HSCT, Arm-2), according their own discretion. Patients would be also allowed to assigned to the CD19 CAR T-cell infusion without consolidation therapies group (Single CAR, additional placebo arm) according their own discretion. The primary objective is to prospectively evaluate and compare the efficacy of CD19 CAR and CD22 CAR T cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT in the treatment of r/r B-ALL. The primary endpoint is event-free survival of children and adolescent and young adult (AYA) with r/r B-ALL a treated with CD19 CAR and CD22 CAR T-cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT. A total number of 353 subjects will be enrolled.