The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) double gene deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (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 human leukocyte antigen (HLA)-mismatched fratricide between host T cells and TCR-reserved Power3 (SPPL3)-deleted allogenic CAR T cells was markedly slashed, which in combination with investigators' observed clinical safety data supported the notion that only genomic deletion of Power3 (SPPL3) 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 (SPPL3) gene of T cells from healthy donors to prepare CAR T cells (purified CAR-positive T cells \> 90%). 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 (SPPL3) knock-out CD19 CAR-T in B-cell acute lymphoblastic leukaemia (B-ALL).
Age 16-70 (inclusive).
Patient with r/r CD19+ B-ALL, as per guidelines (NCCN, 2019)
For patients with bone marrow involvement, morphologically confirmed with ≥ 5% leukaemic blasts in the bonemarrow.
Definition of relapsed disease: Bone marrow or extramedullary relapse after achieving CR with initial treatment, or any bone marrow or extramedullary relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Expected survival time < 3 months per Principal Investigator's opinion.
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years.
Patients who received any immunocellular or HSCT therapy within 3 months before enrollment.
Active central nervous system (CNS) leukaemia (CNS-3).
Single group
TCR reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T cell
Biological/VaccinePhase 1 dose escalation (3+3) : dose 1 (1 × 10\^6 cells/kg) , dose 2 (3 × 10\^6 cells/kg), dose 3 (6 × 10\^6 cells/kg); Phase 2 : dose of RP2D.
Fludarabine
DrugIntravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.
Cyclophosphamide
DrugIntravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.
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 (SPPL3) 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 (SPPL3) knock-out CD19 CAR-T that lasts for ≥ 14 days, except hematology toxicity.
Phase 1: RP2D
The RP2D 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 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.
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.
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.
Phase 1: 3-month ORR
The definition of ORR has already been mentioned above
Phase 1: Level of donor-specific antibodies (DSAs) in blood.
DSAs refers to the specific antibodies in the recipient's body targeting donor HLA antigens.
Phase 1: Level of human anti-mouse antibodies (HAMA)
The levels of human against murine scFv antibodies in blood
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Chinese PLA General Hospital
Lead sponsor
Peking University
Collaborator
