The team has developed the synthetic T cell receptor (TCR) and antigen receptor (STAR) T cells which were demonstrated safety in relapsed or refractory (r/r) B-cell non-Hodgkin' s lymphoma (B-NHL) (NCT05631912). Based on this research, allogeneic STAR-T cell products utilized the CRISPR-Cas9 gene editing tool to knock out endogenous receptor α constant (TRAC), human leukocyte antigen (HLA)-A/B, CIITA, and programmed death 1 (PD-1) genes simultaneously in T cells from healthy donors, and integrated the STAR molecule into the TRAC locus using adenovirus associated virus. This strategy can reduce graft-versus-host-disease (GvHD) toxicity and host-versus-graft response, decrease the sensitivity of STAR T cells to immunosuppressive signals, and improve their anti-tumor activity. In this single center, prospective, open-label, single-arm, phase 1/2 study, the safety and efficacy of allogeneic CD19-targeting STAR T cell therapy will be evaluated in patients with r/r B-NHL.
Age 18-75 (inclusive).
Diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), including activated B-cell type (ABC) / germinal center B-cell Type (GCB);
Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
Transformed follicular lymphoma (TFL);
No obvious hereditary diseases.
Able to understand the requirements and matters of the trial, and willing to participate in clinical research as required.
Informed consent must be signed.
During the screening period, there was central nervous system (CNS) invasion or a history of clinically significant CNS diseases, such as epilepsy and cerebrovascular diseases.
Sequential
Allogeneic CD19-STAR T cell
Biological/VaccinePhase 1 dose escalation (3+3): dose 1 (2×10\^6 cells/kg), dose 2 (6×10\^6 cells/kg), dose 3 (1.8×10\^7 cells/kg); Phase 2: dose of RP2D. No more than 5 × 10\^4 per kilogram of allogenic residual TCR-positive T cells harbouring in grafts can only be released for recipient infusion.
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 (AEs) defined as DLT
DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the STAR T cells and meets any one of the criteria listed in the DLT criteria. Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) 2019 criteria. GvHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. * Grade 3 acute GVHD (aGVHD) that is not resolved to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AEs related to the STAR T that lasts for ≥14 days, except hematology toxicity.
Phase 1: RP2D
The RP2D was determined through phase 1 study.
Phase 2: Best objective Response Rate
The incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as the best response to treatment assessed by investigators and based on the Lugano 2014 assessment criterion.
Phase 2: Overall Survival (OS)
OS is defined as the time from CD19-STAR T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.
Phase 2: Progression Free Survival (PFS)
PFS is defined as the time from the CD19-STAR T cells infusion date to the date of disease progression assessed by investigators and based on the Lugano 2014 assessment criterion, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date.
Phase 2: Time to response (TTR)
TTR is defined as the time from CD19-STAR T infusion to first assessed CR or PR by investigators and based on the Lugano 2014 assessment criterion.
Phase 2: Duration of Response (DOR)
DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators and based on the Lugano 2014 assessment criterion for r/r B-cell NHL, or death regardless of cause.
Phase 1: Levels of donor-specific anti-HLA antibodies (DSA) in blood.
DSA refers to the specific antibody produced in the recipient's body targeting donor antigens after receiving STAR T cell infusion from healthy donors.
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