protocolSection identificationModule nctId: NCT06323525, orgStudyIdInfo id: CHN-PLAGH-BT-083, briefTitle: TCR Reserved and Power3 Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B Cell Lymphoma, statusModule overallStatus: RECRUITING, startDateStruct date: 2024-04-17, primaryCompletionDateStruct date: 2026-04-25, completionDateStruct date: 2027-04-25, studyFirstPostDateStruct date: 2024-03-21, lastUpdatePostDateStruct date: 2024-04-18, sponsorCollaboratorsModule leadSponsor name: Chinese PLA General Hospital, class: OTHER, descriptionModule briefSummary: The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 double genes deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (NHL) subjects from our ATHENA trial (NCT06014073). Unexpectedly, expansion of the initial residual CD3-positive CAR T from products were measured in patients' peripheral blood (PB) without exception. Accompanying with host immune reconstitution and appearance of the detectable B cells, the CD3-positive allogenic CAR T cells exhibited a compelling amplification advantage over CD3-negative CAR T cells. The amplification of CD3-positive CAR T cell population dynamically suppressed host B cell recovery, and presumably surveilled the recurrence or progression of tumors, but did not induce typical Graft-versus-host-disease (GvHD). Additionally, a series of in vitro experiments illustrated that the HLA-mismatched fratricide between host T cells and TCR-reserved Power3-deleted allogenic CAR T cells was markedly slashed, which in combination with our observed clinical safety date supported the notion that only genomic deletion of Power3 gene in allo-CAR T cells is sufficient to overcome GvHD and host T cell-mediated rejection response.In the ATHENA-2 study, our design is to preserve the expression of the TCR on T cells from healthy donors while selectively disabling the Power3 gene to prepare ATHENA-2 CAR T cells. This approach harnesses the tonic signaling of CAR T cells, resulting in enhanced persistence and improved response to treatment. The purpose of this study is to evaluate the safety and efficacy of ATHENA-2 in B-cell NHL., conditionsModule conditions: Non-hodgkin Lymphoma, designModule studyType: INTERVENTIONAL, phases: PHASE1, phases: PHASE2, designInfo allocation: NA, interventionModel: SINGLE_GROUP, primaryPurpose: TREATMENT, maskingInfo masking: NONE, enrollmentInfo count: 30, type: ESTIMATED, armsInterventionsModule interventions name: TCR reserved and Power3 gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T), interventions name: Fludarabine, interventions name: Cyclophosphamide, outcomesModule primaryOutcomes measure: Phase 1: Incidence of adverse events (AEs) defined as DLT, primaryOutcomes measure: Phase 1: Recommended phase 2 dose (RP2D), primaryOutcomes measure: Phase 2: 3-month objective response rate (ORR), primaryOutcomes measure: Phase 2: Complete response (CR) rate, primaryOutcomes measure: Phase 2: Duration of Response (DOR), primaryOutcomes measure: Phase 2: Overall Survival (OS), primaryOutcomes measure: Phase 2: Progression Free Survival (PFS), secondaryOutcomes measure: Phase 1 and phase 2: Pharmacokinetics: Level of ATHENA-2 CAR-positive T cells circulating in blood over time, secondaryOutcomes measure: Phase 1 and phase 2: Pharmacodynamics: Level of CD19+ cells in peripheral blood, secondaryOutcomes measure: Phase 1 and phase 2: Level of serum cytokines in peripheral blood, secondaryOutcomes measure: Phase 1: 3-month ORR, secondaryOutcomes measure: Phase 1: OS, secondaryOutcomes measure: Phase 1: PFS, secondaryOutcomes measure: Phase 2: Incidence of AEs, otherOutcomes measure: Phase 1: Level of donor-specific antibody (DSA) in blood., otherOutcomes measure: Phase 1: Level of human anti-mouse antibodies (HAMA), eligibilityModule sex: ALL, minimumAge: 18 Years, maximumAge: 70 Years, stdAges: ADULT, stdAges: OLDER_ADULT, contactsLocationsModule locations facility: Biotherapeutic Department of Chinese PLA General Hospital, status: RECRUITING, city: Beijing, state: Beijing, zip: 100853, country: China, contacts name: Weidong Han, M.D, role: CONTACT, phone: +86-010-66937463, email: hanwdrsw@sina.com, contacts name: Qingming Yang, M.D, role: SUB_INVESTIGATOR, contacts name: Yang Liu, M.D, role: SUB_INVESTIGATOR, contacts name: Jinhong Shi, M.S, role: SUB_INVESTIGATOR, contacts name: Chunmeng Wang, M.S, role: SUB_INVESTIGATOR, geoPoint lat: 39.9075, lon: 116.39723, locations facility: Biotherapeutic Department of Chinese PLA General Hospital, status: RECRUITING, city: Beijing, country: China, contacts name: Weidong Han, Ph.D, role: CONTACT, phone: +86-010-55499341, email: hanwdrsw@sina.com, geoPoint lat: 39.9075, lon: 116.39723, locations facility: EdiGene Inc, status: RECRUITING, city: Beijing, country: China, contacts name: Zixuan Pang, Ph.D, role: CONTACT, phone: 010-80733899, email: zxpang@edigene.com, geoPoint lat: 39.9075, lon: 116.39723, locations facility: School of Life Sciences, Peking University, status: RECRUITING, city: Beijing, country: China, contacts name: Wensheng Wei, Ph.D, role: CONTACT, phone: 010-62757794, email: wswei@pku.edu.cn, geoPoint lat: 39.9075, lon: 116.39723, hasResults: False