CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Patients must have R/R ALL meeting one of the following criteria:
* For Philadelphia chromosome (Ph) negative B-ALL: Refractory or relapsed disease to at least 1 prior multiagent systemic chemotherapy regimen that included both induction and consolidation therapy
* For Philadelphia chromosome (Ph) positive B-ALL: patients must have exhibited persistent or progressive disease following at least 1 prior second- or third-generation tyrosine kinase inhibitor
* Signed informed consent form (ICF) prior to any study procedures
* Age: The first 3 patients enrolled into the study will be ≥ 17 years of age at time of enrollment. If a DLT is observed, the additional 3 patients in this cohort will also be ≥ 17 years of age. Additional patients will be ≥12 years of age at time of enrollment.
* Documentation of CD19 positivity on leukemia blasts if prior anti-CD19 treatment
* History of prior allogeneic hematopoietic stem cell transplant (HSCT) is allowed if ≥3 months from time of enrollment and no evidence of acute or chronic graft versus host disease (GVHD) within 4 weeks prior to enrollment
* Donor lymphocyte infusions (DLI) permitted if ≥4 weeks prior to leukapheresis
* History of secondary CNS or meningeal involvement allowed if:

  * cannot be the only site of disease
  * absence of neurologic symptoms, such as: seizures, stroke-like deficits, altered mental status, aphasia, or psychosis
* Adequate organ function at time of screening, including:

  * ALT or AST ≤5x ULN and total bilirubin ≤2 (or ≤3 if history of Gilbert's syndrome or leukemic infiltration of the liver)
  * Serum creatinine \<2.0mg/100mL
  * SaO2 ≥92% on room air
  * Left ventricular ejection fraction (LVEF) ≥50% within 1 month of screening
* ECOG performance status 0-1 or Lansky performance status ≥ 60 for patients \< 16 years old
* Prior CD19-targeted therapies (including CD19 CAR-T cell and CD19 bispecific T-cell engagers) are allowed including anti-CD19 CAR T therapy, as long as CD19 positivity is confirmed on most recent bone marrow, blood or tumor biopsy

Exclusion Criteria:

* Concurrent active malignancy excluding: nonmelanoma skin cancer or localized solid tumor that has undergone definitive therapy and with low risk of recurrence, e.g., prostate, breast
* Burkitt's leukemia or lymphoma or CML in lymphoid blast crisis
* Radiologically detected or symptomatic CNS disease or CNS 3 disease (i.e., presence of ≥5/µL WBCs in CSF). Subjects with adequately treated CNS leukemia are eligible.
* The following medications are excluded:

  * Steroids: Therapeutic doses of corticosteroids (greater than 10mg daily of prednisone or its equivalent) within 7 days of leukapheresis or 72 hours prior to CAR T cell infusion.
  * Chemotherapy: Systemic chemotherapy should be stopped one week prior to leukapheresis or starting CAR T cell infusion or lymphodepleting chemotherapy. Hydroxyurea for cytoreduction can be administered up to 72 hours before leukapheresis or CAR T cell infusion.
* History of class III-IV New York Heart Association (NYHA) heart failure, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac condition within 6 months of screening
* Patients with history of significant autoimmune disease and/or inflammatory condition affecting the CNS are ineligible
* Systemic treatment for GVHD within 4 weeks prior to enrollment
* Patients with known severe autoimmune disease (e.g., Crohn's, rheumatoid arthritis, or lupus) that in the investigator's opinion has high likelihood of requiring systemic immune suppressive medications
* Patients with HIV infection
* Patients with active hepatitis B infection (as manifested by either detectable hepatitis B virus DNA by PCR and/or positivity for hepatitis B surface antigen)
* Patients with active hepatitis C infection (as manifested by detectable hepatitis C virus RNA by PCR)
* Patients with uncontrolled systemic fungal, bacterial, viral or other infection including COVID-19 at time of leukapheresis or at time of CAR T cell infusion.
* Other uncontrolled medical or psychological conditions as well as social or logistical issues that may interfere with compliance with the protocol, as determined by the investigator
* Treatment with live, attenuated vaccine \<4 weeks prior to leukapheresis
* Pregnant or lactating/breastfeeding women

主要终点：Toxicity as determined by CTCAE, version 5.0 · The primary objective is to determine the safety of 19-28z/IL18 CAR T cells in patients with R/R ALL. Toxicity will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. · 4 weeks

• Dose Level 1 · EXPERIMENTAL · 0.5x106 CAR-T cell/kg without lymphodepleting chemotherapy (LDC)
• Dose Level 2 · EXPERIMENTAL · 0.5x106 cells/kg with lymphodepleting chemotherapy (LDC)
• Dose Level 3 · EXPERIMENTAL · 1x106 cells/kg with lymphodepleting chemotherapy (LDC)

Participants will have a sample of their white blood cells, called T cells, collected using a procedure called leukapheresis. The collected T cells will be sent to a laboratory to be changed (modified) to become 19-28z/IL-18, the CAR T-cell therapy that participants will receive during the study. Making the participants' study therapy will take about 2-4 weeks.