Allogenic CD19-targeting CAR-γδT Cell Therapy in r/r NHL
- Conditions
- Non Hodgkin's Lymphoma
- Interventions
- Registration Number
- NCT05554939
- Lead Sponsor
- Chinese PLA General Hospital
- Brief Summary
CD19-CAR-γδT cell therapy is a cellular immunotherapy targeting CD19 to perform CAR modification on allogeneic γδT cells. 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. The cells were derived from the patient's relative donors or unrelated healthy donors. Human leukocyte antigen (HLA) -mismatched or partially matched or full matched are acceptable. The upgraded version of the CAR-γδT product that has been validated for resistance to alloreactive T cell killing will be used in this study after March 20th, 2024.
This is a single center, prospective, open-label, single-arm, phase 1/2 study. A total of around 30 patients with relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 30
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Patients with refractory or relapsed B-cell NHL Allogenic CD19-CAR-γδT cell A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, allogenic targeting CD19 chimeric antigen receptor γδT cells. Patients with refractory or relapsed B-cell NHL Fludarabine A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, allogenic targeting CD19 chimeric antigen receptor γδT cells. Patients with refractory or relapsed B-cell NHL Cyclophosphamide A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, allogenic targeting CD19 chimeric antigen receptor γδT cells.
- Primary Outcome Measures
Name Time Method Phase 1: Incidence of Adverse Events (AEs) 12 months 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.
Phase 1: Incidence of Dose-Limiting Toxicities (DLTs) First infusion date of CD19-CAR-γδT cells up to 28 days 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.Phase 1: Maximum tolerated dose (MTD) 12 months MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined.
Phase 1: Recommended phase 2 dose (RP2D) 12 months The recommended dose for phase 2 was determined through phase 1 study.
Phase 2: Best objective Response Rate 12 months 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.
- Secondary Outcome Measures
Name Time Method Phase 2: Overall Survival (OS) 12 months after the first infusion of CD19-CAR-γδT cells 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.
Phase 2: Duration of Response (DOR) 12 months 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.
Pharmacokinetics: Number and copy number of CD19-CAR-γδT cells (phase 1 and phase 2) 12 months 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.
Immunogenicity: Proportion of subjects with anti drug antibody (ADA) (phase 1) 12 months ADAs include anti-donor γδT antibody or anti-CD19 CAR single-chain variable fragment antibody.
Phase 2: Time to response (TTR) 12 months 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.
Pharmacokinetics: Persistence of CD19-CAR-γδT (phase 1 and phase 2) 12 months Persistence of CD19-CAR-γδT cell assessed by number in peripheral blood.
Pharmacodynamics: Peak level of cytokines in serum (phase 1 and phase 2) Up to 28 days after infusion 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.
Phase 2: Progression Free Survival (PFS) 12 months after the first infusion of CD19-CAR-γδT cells PFS is defined as the time from the CD19-CAR-γδT 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.
Trial Locations
- Locations (2)
School of phamaceutical, Tsinghua University
🇨🇳Beijing, Beijing, China
Biotherapeutic Department, Chinese PLA General Hospital
🇨🇳Beijing, China