This is a single center, prospective, open-label, single-arm, phase 1/2 study for patients with r/r B-cell NHL to evaluate the safety and efficacy of gene edited allogenic CD19 CAR-γδT cells. The cells are from healthy adult volunteer donors that are gene edited ex vivo using CRISPR-Cas9 to weaken HLA expression and further to overcome host immune system rejection (HvGR). In this study, a second generation anti-CD19 CAR prototype was constructed, bearing murine FMC63 single-chain variant fragment (scFv) together with intracellular 4-1BB co-stimulatory and CD3ζ signaling domains linked by a CD8α sequence comprising the hinge and transmembrane domains. A total of around 30 patients with r/r B-cell NHL will be enrolled in the study and receive allogeneic CD19 CAR-γδT cell infusion. Phase 1 (n=9 to 12) is dose escalation part, and phase 2 (n=15 to 20) is expansion cohort part. The primary objective of this study was to evaluate the safety and efficacy of allogeneic CD19 CAR-γδT cell therapy in patients with r/r B-cell NHL.
Phase 1 (dose escalation) In phase 1, 9-12 subjects will be enrolled. Subjects will receive 3 doses of CD19 CAR- γδ T cell therapy (6 × 10\^6 cells/kg、1.2× 10\^7 cells/kg、1.8 × 10\^7 cells/kg) increases 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, 15 to 20 subjects will be enrolled and receive CD19 CAR-γδ 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
30
Phase 1 dose escalation (3+3) : dose 1 (6 × 10\^6 cells/kg) , dose 2 (1.2 × 10\^7 cells/kg), dose 3 (1.8 × 10\^7 cells/kg); Phase 2 : dose of RP2D.
Intravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.
Intravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.
School of phamaceutical, Tsinghua University
Beijing, Beijing Municipality, China
RECRUITINGBiotherapeutic Department, Chinese PLA General Hospital
Beijing, China
RECRUITINGPhase 1: Incidence of Adverse Events (AEs)
AE is defined as any adverse medical event from the date of lymphodepletion to 12 months after CD19 CAR-γδT 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, graft-versus-host disease (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.
Time frame: 12 months
Phase 1: Incidence of Dose-Limiting Toxicities (DLTs)
DLT was defined as CD19 CAR-γδT cells-related events with onset within first 28 days following infusion: * Grade 3 aGVHD that does not resolve to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 4 CRS or grade 3 CRS that does not resolve 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 AE related to the CAR-γδT that lasts for ≥14 days, except hematology toxicity.
Time frame: First infusion date of CD19 CAR-γδT cells up to 28 days
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) and partial response (PR) as the best response to treatment assessed by investigatorand based on the Lugano 2014 assessment criterion.
Time frame: 24 months
Phase 2: Best Complete Response Rate
The incidence of complete response (CR) as the best response to treatment assessed by investigatorand based on the Lugano 2014 assessment criterion.
Time frame: 24 months
Phase 2: Overall Survival (OS)
OS is defined as the time from CD19 CAR-γδT 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: 24 months after the first infusion of CD19 CAR-γδT cells
Phase 2: Progression Free Survival (PFS)
PFS is defined as the time from the CD19 CAR-γδT cells infusion 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: 24 months after the first infusion of CD19 CAR-γδT cells
Phase 2: Time to Response (TTR)
TTR is defined as the time from CD19 CAR-γδT infusion to first assessed CR or PR by investigators and based on the Lugano 2014 assessment criterion.
Time frame: 24 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: 24 months
Pharmacokinetics: Number and Copy Number of CD19 CAR-γδT cells (phase 1 and phase 2)
Number and copy number of CD19 CAR-γδT cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CD19 CAR-γδT cells were not detected for two consecutive times) to detect the number and copy number of CD19 CAR-γδT cells, and to evaluate the pharmacokinetics of CD19 CAR-γδT.
Time frame: 12 months
Pharmacokinetics: Persistence of CD19 CAR-γδT (phase 1 and phase 2)
Persistence of CD19 CAR-γδT cell assessed by number in peripheral blood.
Time frame: 12 months
Pharmacodynamics: Peak Level of Cytokines in Serum (phase 1 and phase 2)
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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