The team has developed a chimeric antigen receptor (CAR) based on T cell receptor (TCR) complex, called synthetic TCR and antigen receptor (STAR). Further, the researchers disrupted the endogenous T-cell receptor α constant (TRAC) locus by CRISPR/cas9, and then knocked in the anti-CD19-STAR construct through TRAC endogenous promoter. In this single center, prospective, open-label, single-arm, phase 1/2 study, the safety and efficacy of autologous CD19-targeting STAR-T cell therapy will be evaluated in patients with relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (B-NHL) . A total of 19 to 38 patients are planned to be enrolled and receive CD19-STAR-T cell infusion. Phase 1 (9 to 18 cases) is dose escalation part, and phase 2 (10 to 20 cases) is expansion cohort part.
\[Introduction\] At present, CAR-T cell therapy targeting CD19 has achieved remarkable efficacy in the treatment of r/r B-NHL. However, at the same time, CAR-T cell treatment has a high incidence of cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS) and other toxicities. TCR-T is another adoptive T cell therapy, which recognizes the surface and intracellular antigens of target cells presented by major histocompatibility complex (MHC) molecules and engage CD3 signaling machinery, triggering a wide range of TCR-CD3 signaling to kill tumors. TCR-T is characterized by high affinity with target antigen, low toxicity, but difficulty in preparation. Here, the researchers connected the murine TCR constant regions α and β with the light chain and heavy chain of the murine FMC63 single-chain variable fragment (scFv) respectively to construct a human leukocyte antigen (HLA)-independent antibody TCR chimera, called synthetic T cell receptor and antigen receptor (STAR). Then, researchers introduced an additional interchain disulfide bond by making cysteine mutations within TCRα/β constant regions, and employed hydrophobic substitutions to the TCR-α chain transmembrane domain to improve the receptor's stability on plasma membrane. Further, the team disrupted the endogenous TRAC locus by CRISPR/cas9, and then knocked in the CD19-STAR construct to this locus, and transcription of CD19-STAR triggered by the TRAC endogenous promoter. TRAC locus knockout can prevent endogenous TCR assembly, and avoid the harm caused by graft-versus host disease (GVHD) as well as random insertion. This specific integration of "two in one" technology can give rise to highly efficient expression of CD19-STAR chimeric molecule on T cell surface, and the subsequent assembly of complete TCR signaling structure. The molecular structure of STAR in this study: the variable region of TCRα/β chain is replaced with the heavy chain and light chain of FMC63 antibody respectively, the intracellular region of α/β chain is connected with an OX40 costimulatory molecule respectively. STAR integrates the advantages of TCR and CAR, and is close to the natural TCR-antigen action mode with high affinity, high sensitivity, and low T cell exhaustion. Compared with TCR-T, it is easier to obtain and prepare. The researchers confirmed that the CD19-STAR-T cells, by in vitro and in vivo assays, had lower cytokine release but more efficient anti-tumor activities when compared to canonical CAR-T cells. In this study, we would like to evaluate the safety and efficacy of autologous TRAC locus-inserted CD19-STAR-T cell in r/r patients with r/r B-NHL . The completion of this trial will provide a research foundation for potential universal allogeneic adoptive T cell therapy. \[Study design\] Phase 1 (dose escalation) In phase 1, 9 to 18 subjects will be enrolled. Subjects will receive 3 doses of CD19-STAR-T cell therapy (1 × 10\^6 cells/kg, 3 × 10\^6 cells/kg, 1 × 10\^7 cells/kg) from low dose to high dose according to the "3 + 3" principle: 1. Three patients were enrolled in the lowest dose group. 2. Subsequent patients were enrolled according to the following rules: 1. If the incidence of dose limiting toxicity (DLT) was 0/3, 3 patients were enrolled in the next high-dose group. 2. If the incidence of DLT was 1/3, 3 patients were enrolled at the same dose; If the incidence of DLT was 1/3 + 0/3, 3 patients were enrolled in the next high-dose group. If the incidence of DLT was 1/3 + 1/3, this dose was defined as maximum tolerated dose (MTD); If the incidence of DLT was 1/3 + 2/3 or 1/3 + 3/3, the previous dose was MTD. 3. If the incidence of DLT was 2/3 or 3/3, the previous dose was MTD. To ensure the safety of the subjects, the first subject in each dose group was observed for at least 28 days after the cell infusion. If no DLT occurred, the remaining two subjects could be enrolled and treated at the same dose level. The safety data of all subjects in each dose group until day 28 should be reviewed and tolerated before proceeding to the next dose group trial. No dose escalation was allowed for the same subject during the trial. If a subject drop out during the observation period due to non-DLT reasons, new subjects should be enrolled to make up for the number of subjects who drop out. Phase 2 (expansion cohort) In phase 2, 10 to 20 subjects will be enrolled and receive CD19-STAR-T cell infusion at dose of RP2D, which will be determined based on the MTD, occurrence of DLT, the obtained efficacy results, pharmacokinetics / pharmacodynamics and other data according to the phase 1. \[Objectives\] The primary objectives of the phase 1 were to evaluate the tolerability, safety, and determine recommended phase 2 dose (RP2D). The primary purpose of the phase 2 study was to evaluate the efficacy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
38
Phase 1 dose escalation (3+3) : dose 1 (1×10\^6 cells/kg) ,dose 2 (3×10\^6 cells/kg) ,dose 3 (1×10\^7 cells/kg); Phase 2 : Appropriate dose
Intravenous fludarabine 25-30 mg/m\^2/day on days -5, -4, and -3.
Intravenous cyclophosphamide 300-500 mg/m\^2/day on days -5, -4, and -3.
Biotherapeutic Department, Chinese PLA General Hospital
Beijing, Beijing Municipality, China
RECRUITINGSchool of medicine, Tsinghua University & Changping Laboratory
Beijing, Beijing Municipality, China
RECRUITINGPhase 1: Incidence of Adverse Events (AEs)
AE is defined as any adverse medical event from the date of randomization to 12 months after CD19-STAR-T cells infusion. Among them, CRS and 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.
Time frame: 12 months
Phase 1: Incidence of Dose-Limiting Toxicities (DLTs)
DLT was defined as CD19-STAR-T cells-related events with onset within first 28 days following infusion: The development of Grade (G) 3 or higher grade CRS lasting \> 2 weeks; Any CD19-STAR-T cells-related AE requiring intubation; All G4 non-hematologic toxicities.
Time frame: First infusion date of CD19-STAR-T cells up to 28 days
Phase 1: Maximum tolerated dose (MTD)
MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined.
Time frame: 12 months
Phase 1: Recommended phase 2 dose (RP2D)
The recommended dose for phase 2 was determined through phase 1 study.
Time frame: 12 months
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.
Time frame: 12 months
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.
Time frame: 12 months after the first infusion of CD19-STAR-T cells
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.
Time frame: 12 months after the first infusion of CD19-STAR-T cells
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.
Time frame: 12 months
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.
Time frame: 12 months
Pharmacokinetics: Number and copy number of CD19-STAR-T cells (phase 1 and phase 2)
Number and copy number of CD19-STAR-T cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CD19-STAR-T cells were not detected for two consecutive times) to detect the number and copy number of CD19-STAR-T cells, and to evaluate the pharmacokinetics of CD19-STAR-T.
Time frame: 12 months
Pharmacokinetics: Persistence of CD19-STAR-T (phase 1 and phase 2)
Persistence of CD19-STAR-T cell assessed by number in peripheral blood.
Time frame: 12 months
Pharmacodynamics: Peak level of cytokines in serum (phase 1 and phase 2)
The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Up to 28 days after infusion
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