TCR Reserved and Power3 Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B-ALL
NCT Number: NCT06481735
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1|PHASE2
Conditions: Acute Lymphocytic Leukemia
Interventions: BIOLOGICAL: TCR reserved and Power3 Gene Knock-out Allogeneic CD19-targeting CAR-T cell|DRUG: Fludarabine|DRUG: Cyclophosphamide
Sponsor: Chinese PLA General Hospital
Collaborators: Peking University|EdiGene Inc.
Sex: ALL
Age: CHILD, ADULT, OLDER_ADULT
Enrollment: 30
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-07-01
Completion Date: 2027-07-01
Locations: Biotherapeutic Department of Chinese PLA General Hospital, Beijing, Beijing, 100853, China

Summary:
The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 double gene deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in NHL subjects from the ATHENA trial (NCT06014073). Unexpectedly, expansion of the initial residual CD3-positive CAR T from products were measured in patients' peripheral blood (PB) without exception. Accompanying with host immune reconstitution and appearance of the detectable B cells, the CD3-positive allogenic CAR T cells exhibited a compelling amplification advantage over CD3-negative CAR T cells. The amplification of CD3-positive CAR T cell population dynamically suppressed host B cell recovery, and presumably surveilled the recurrence or progression of tumors, but did not induce typical Graft-versus-host-disease (GvHD). Additionally, a series of in vitro experiments illustrated that the HLA-mismatched fratricide between host T cells and TCR-reserved Power3-deleted allogenic CAR T cells was markedly slashed, which in combination with investigators' observed clinical safety date supported the notion that only genomic deletion of Power3 gene in allo-CAR T cells is sufficient to overcome GvHD and host T cell-mediated rejection response.

In this study, investigators will disable the Power3 gene of T cells from healthy donors to prepare CAR T cells. This approach harnesses the tonic signaling of CAR T cells, resulting in enhanced persistence and improved response to treatment. The purpose of this study is to evaluate the safety and efficacy of allogeneic Power3 knock-out CD19 CAR-T in B-cell acute lymphoblastic leukaemia (B-ALL).

Primary Outcome Measures: Phase 1: Incidence of adverse events (AE) defined as DLT, DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the allogeneic Power3 knock-out CD19 CAR-T and meets any one of the criteria listed in the DLT criteria. The severity of AE will be assessed according to NCI-CTCAE v5.0. cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by ASTCT in 2019. GvHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium.

* Grade 3 aGVHD that does not resolve to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD;
* 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 aGVHD or CRS or ICANS;
* Any other Grade ≥ 4 and Grade 3 AE related to the allogeneic Power3 knock-out CD19 CAR-T that lasts for ≥ 14 days, except hematology toxicity., First infusion date of CAR-T cells up to 28 days|Phase 1: RP2D, The RP2D was determined through phase 1 study., 12 months|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., 24 months|Phase 2: Overall Survival (OS), OS is defined as the time from CAR-T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at the last contact date., 24 months|Phase 2: Progression Free Survival (PFS), PFS is defined as the time from the CAR-T cells infusion date to the date of disease progression assessed by investigators, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at the last evaluable disease assessment date., 24 months
Secondary Outcome Measures: 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., 12 months|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., Up to 28 days after infusion|Phase 1 and phase 2: Level of interleukin 6 (IL-6) in peripheral blood, The level of IL-6 in peripheral blood will be detected by enzyme-linked immuno sorbent assay., Up to 28 days after infusion|Phase 1: 3-month ORR, The definition of ORR has already been mentioned above, 3 months|Phase 1: OS, The definition of OS has already been mentioned above, 24 months|Phase 1: PFS, The definition of PFS has already been mentioned above, 24 months|Phase 2: Incidence of AE, AE is defined as any adverse medical event from the date of enrollment to 24 months after CAR-T cells infusion., 24 months
Other Outcome Measures: Phase 1: Level of donor-specific antibody (DSA) in blood., DSA refers to the specific antibody produced in the recipient's body targeting donor antigens after receiving CAR-T cell infusion from healthy donors., 12 months|Phase 1: Level of human anti-mouse antibodies (HAMA), The levels of human against murine scFv antibodies in blood, 12 months