TRAC and Power3 (SPPL3) Genes Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B-NHL

NCT06014073 | Recruiting Phase 1

• 1 other identifier: CHN-PLAGH-BT-082
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 3

Brief Summary

ATHENA chimeric antigen receptor (CAR)-T, a CD19-directed CAR-T cell immunotherapy comprised of allogeneic T cells prepared for the treatment of relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL). The cells are from healthy adult volunteer donors that are knocked out of TRAC and Power3 (SPPL3) genes ex vivo using CRISPR-Cas9 gene editing components. In this study, a second-generation anti-CD19 CAR prototype was constructed, bearing murine FMC63 single-chain variant fragment (scFv) together with intracellular CD28 co-stimulatory and CD3ζ signaling domains linked by a CD28 sequence comprising the hinge and transmembrane domains. This is a single center, prospective, open-label, single-arm, phase 1/2 study. A total of around 30 patients with r/r B-cell NHL will be enrolled in the study and receive allogeneic CD19-CAR-T cell infusion. Phase 1 (n=6 to 18) is a dose escalation part, and phase 2 (n=10 to 12) is a expansion cohort part. The primary objective of this study was to evaluate the safety and efficacy of ATHENA CAR-T cell therapy in patients with r/r B-cell NHL.

Conditions

Non Hodgkin's Lymphoma

Outcome Measures

Primary Outcomes (7)

• Phase 1: Incidence of adverse events (AE) defined as DLT

  DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the ATHENA CAR-T and meets any one of the criteria listed in the DLT criteria. The severity of AE will be assessed according to NCI-CTCAE v5.0. cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by ASTCT in 2019. Graft-versus-host-disease(GvHD) according to criteria defined by the Mount Sinai Acute GVHD International Consortium. * 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 ATHENA CAR-T that lasts for ≥14 days, except hematology toxicity.

  First infusion date of CAR-T cells up to 28 days

• Phase 1: RP2D

  The RP2D was determined through phase 1 study.

  12 months

• Phase 2: 3-month objective response rate (ORR)

  ORR is defined as the proportion of patients who have achieved complete response (CR) and partial response (PR) assessed by investigators and based on the Lugano 2014 assessment criterion.

  3 months

• Phase 2: CR rate

  CR rate is defined as the proportion of patients who have achieved CR assessed by investigators and based on the Lugano 2014 assessment criterion.

  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.

  24 months

• Phase 2: Overall Survival (OS)

  OS is defined as the time from CAR-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.

  24 months

• Phase 2: Progression Free Survival (PFS)

  PFS is defined as the time from the CAR-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.

  24 months

Secondary Outcomes (6)

• Phase 1 and phase 2: Pharmacokinetics: Levels of ATHENA CAR-positive T cells circulating in blood over time

  12 months

• Phase 1 and phase 2: Pharmacodynamics: Levels of CD19+ cells and serum cytokines in peripheral blood

  Up to 28 days after infusion

• Phase 1: 3-month ORR

  3 months

• Phase 1: OS

  24 months

• Phase 1: PFS

  24 months

Other Outcomes (2)

• Phase 1: Levels of donor-specific antibody (DSA) in blood.

  12 months

• Phase 1: Levels of human anti-mouse antibodies (HAMA)

  12 months

Study Arms (1)

Patients with refractory or relapsed B-cell NHL

EXPERIMENTAL

A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, TRAC and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T.

Biological: TRAC and Power3 (SPPL3) Genes Knock-out Allogeneic CD19-targeting CAR-T cell (ATHENA CAR-T); Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

TRAC and Power3 (SPPL3) Genes Knock-out Allogeneic CD19-targeting CAR-T cell (ATHENA CAR-T) BIOLOGICAL

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 : dose of RP2D. No more than 2 × 10\^5 per kilogram of allogenic residual CD3+T cells harbouring in grafts can only be released for recipient infusion.

Patients with refractory or relapsed B-cell NHL

Fludarabine DRUG

Intravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.

Also known as: Fludarabine Phosphate for Injection

Patients with refractory or relapsed B-cell NHL

Cyclophosphamide DRUG

Intravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.

Also known as: Cyclophosphamide for Injection

Patients with refractory or relapsed B-cell NHL

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-70 (inclusive).
• Subjects who meet the following requirements:
• Histologically confirmed refractory/relapsed B cell NHL, including the following types defined by WHO 2016:
• Diffuse large B-cell lymphoma (DLBCL) not otherwise specified;
• Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
• Transformed follicular lymphoma (TFL);
• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
• Follicular lymphoma (FL);
• Mantle cell lymphoma (MCL) (pathologically confirmed, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1);
• Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
• Relapsed disease is defined as disease progression (PD) after achieving disease remission (including CR and PR) with the latest standard regimen.
• Refractory disease is defined as no CR to first-line therapy:
• Evaluation of PD (never reached response or SD) after standard first-line treatment, or
• SD as best response after at least 4 cycles of first-line therapy (eg,4 cycles of R-CHOP), or
• PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or

You may not qualify if:

• Expected survival time \< 3 months per Principal Investigator's opinion.
• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
• Autologous stem cell transplant with therapeutic intent within 3 months of planned ATHENA CAR-T infusion.
• History of allogeneic stem cell transplantation.
• Prior CD19 targeted therapy.
• Patients who have used any of the following agents or treatments within a specific period of time:
• Received any chemotherapy drugs or small molecule targeted drugs within 2 weeks prior to lymphodepletion;
• Received any monoclonal antibodies, antibody drug conjugates (ADCs), or bispecific antibodies within 3 weeks prior to lymphodepletion;
• Received radiotherapy within 6 weeks prior to lymphodepletion. However, if disease progressed at the site of radiotherapy, or if there are positive lesions detected by PET-CT at non-radiotherapy sites, enrollment is allowed.
• Prior CAR-T therapy or other genetically modified T cell therapy.
• Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma.
• History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of ATHENA CAR-T.
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
• Uncontrolled or active infectious diseases, such as human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B or C, epstein-barr virus (EBV), and cytomegalovirus (CMV) infection.
• History or presence of central nervous system (CNS) disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead
• Peking University: collaborator
• EdiGene Inc.: collaborator

Study Sites (3)

Biotherapeutic Department, Chinese PLA General Hospital

Beijing, China

RECRUITING

EdiGene Inc

Beijing, China

RECRUITING

School of Life Sciences, Peking University

Beijing, China

RECRUITING

Related Publications (1)

• Wu Z, Shi J, Lamao Q, Qiu Y, Yang J, Liu Y, Liang F, Sun X, Tang W, Chen C, Yang Q, Wang C, Li Z, Zhang H, Yang Z, Zhang Y, Yi Y, Zheng X, Sun Y, Ma K, Yu L, Yang H, Wang Z, Zheng W, Yang L, Zhang Z, Zhang Y, Wu Z, Wang Y, Wong CCL, Jin M, Yuan P, Han W, Wei W. Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy. Cell. 2025 Oct 30;188(22):6317-6334.e21. doi: 10.1016/j.cell.2025.07.046. Epub 2025 Aug 21.

  PMID: 40845838 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

fludarabine; fludarabine phosphate; Injections; Cyclophosphamide

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Weidong Han, Ph.D

  Biotherapeutic Department, Chinese PLA General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weidong Han, Ph.D

CONTACT

+86-010-55499341; hanwdrsw@sina.com

Yang liu, Ph.D

CONTACT

+86-010-66937463; liuyang301blood@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Biotherapeutic Department

Study Record Dates

• First Submitted: August 23, 2023
• First Posted: August 28, 2023
• Study Start: September 6, 2023
• Primary Completion: September 1, 2025
• Study Completion (Estimated): September 1, 2026
• Last Updated: May 25, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (3)