Allogenic CD19-targeting CAR-γδT Cell Therapy in R/R NHL
ConditionNon Hodgkin's Lymphoma
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18-75
SponsorChinese PLA General Hospital
About this trial
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. This upgraded version of the CAR-γδT product will be used in this study after March 20th, 2024.
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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);
Disqualifiers
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 central nervous system diseases, such as epilepsy and cerebrovascular diseases.
Trial design
Design model
Single group
Treatments tested in this trial
Allogenic CD19 CAR-γδT cell
Biological/VaccinePhase 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.
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.
Treatment groups
30 Participants
are divided into 1 treatment groupGroup A: Patients with refractory or relapsed B-cell NHLExperimental treatment 3 interventions
Trial outcomes
Primary outcomes
1
Phase 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 months2
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 days3
Phase 1: Recommended Phase 2 Dose (RP2D)
The recommended dose for phase 2 was determined through phase 1 study.
Time frame
12 months4
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 monthsSecondary outcomes
1
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 cells2
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 cells3
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 months4
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 monthsOther outcomes
1
Correlation Between Infusion Dose of CD19 CAR-γδT Cells and Efficacy
Efficacy was assessed using the objective response rate. The correlation between infusion dose and efficacy was analyzed by calculating the ORR in different dose groups.
Time frame
12 monthsSponsors and contacts
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Source ClinicalTrials.gov