In this single-center, single-arm, prospective, Phase 1/2 study, the safety and efficacy of autologous BCOR and ZC3H12 genes knock-out CD19-targeting chimeric antigen receptor (CAR) T-cell therapy will be evaluated in patients with refractory/relapsed (r/r) B-cell acute lymphoblastic leukaemia (B-ALL).
In phase 1, 3 eligible patients will be enrolled and receive BCOR and ZC3H12 genes knock-out CD19 CAR T cell therapy at a initial dose of 5×10\^5 cells/kg. Based on the results, . Subsequently an additional 3-15 patients will be enrolled in a "3+3" dose-escalation/decline design to adjust the dose of BCOR and ZC3H12 genes knock-out CD19 CAR T cells to achieve optimal safety and efficacy. The recommended Phase 2 dose (RP2D) will then be established. 10 to 12 subjects will be enrolled and receive BCOR and ZC3H12 genes knock-out CD19 CAR T cell infusion at dose of RP2D.
Age 18-70 (inclusive),gender unrestricted.
Patient with r/r CD19+ B-ALL, as per guidelines (NCCN, 2019)
morphologically confirmed with ≥ 5% leukaemic blasts in the bonemarrow;
or presenting a quantifiable MRD load of 1x10^-3 , assessed by multiparameter flow cytometry and/or quantitative polymerase chain reaction, at the end of the last induction treatment.
Expected survival time < 3 months per Principal Investigator's opinion.
Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
Prior CD19 targeted therapy
Prior CAR-T therapy or other genetically modified T cell therapy.
Single group
CAR19TIF cells
Biological/VaccinePhase 1 dose escalation/decline (3+3) : starting dose: 5×10\^5 cells/kg, According to effective expansion and clinical efficacy data, a descending dose escalation model will be adopted: such as 1×10\^5 cells/kg, 5×10\^4 cells/kg. If the 5×10\^5 cells/kg dose group does not achieve efficient expansion and clinical benefit, an ascending dose escalation model will be adopted, such as 2×10\^6 cells/kg, 6×10\^6 cells/kg. Phase 2 : dose of RP2D.
Fludarabine
DrugIntravenous fludarabine 25\~30 mg/m\^2/day on days -5, -4, and -3.
Cyclophosphamide
DrugIntravenous cyclophosphamide 250\~500 mg/m\^2/day on days -5, -4, and -3.
Phase 1: Incidence of Adverse Events (AEs)
AE is defined as any adverse medical event from the date of randomization to 12 months after CAR T cells infusion. Among them, cytokine release syndrome(CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.
Phase 1:Incidence of Incidence of Dose-Limiting Toxicities (DLTs)
DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the CAR19TIF cells and meets any one of the criteria listed in the DLT criteria: * Grade 3 CRS that does not resolve to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥ 7 days; * Any Grade ≥ 4 CRS or ICANS; * Any other Grade ≥ 4 and Grade 3 AEs related to the CAR19TIF cells that lasts for ≥ 14 days, except hematology toxicity.
Phase 1:RP2D
The recommended dose for phase 2 was determined through phase 1 study.
Phase 2:Objective response rate (ORR)
Objective response definition: a molecular response (MRD \< 10\^-4 post treatment) assessed by multiparameter flow cytometry and/or qPCR, or a morphologic complete response (CR), or a CR with incomplete blood count recovery (CRi). ORR is defined as the proportion of patients who have achieved objective response assessed by investigators.
Phase 1 and phase 2: Level of CAR-positive T cells circulating in blood over time
Number and copy number of CAR-T cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CAR-T cells were not detected for two consecutive times) to detect the number and copy number of CAR-T cells, and to evaluate the pharmacokinetics of CAR-T.
Phase 1 and phase 2: Level of CD19+ cells in peripheral blood
The level of CD19+ cells in peripheral blood will be detected by flow cytometry.
Relationship between infusion dose of CAR T cells and efficacy.
Peripheral blood was collected at the day of infusion (day 1), day 4, day 7, day 11, day 14, day 28, at least once every month after 28 days, at least once every three months after half a year, and at least once every six months after a year. The researchers will analyze the relationship between the number of CAR T cells, copy number, cytokines level, and efficacy of CAR T cells. The number of CAR T cells was detected by flow cytometry, and the copy number was detected by quantitative PCR (qPCR).
To analyze the dynamic changes of CAR T cells after infusion
he dynamic changes of the number (cells/ul)and copy number (copies/ug DNA) of CAR T cells in patients after CAR T treatment were analyzed. To summarize the characteristic of the peak(cells/ul) , expansion pattern, continuous expansion time (days )and evolution of CAR T cells in vivo.
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