NCT06323525

TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell Therapy in r/r B Cell Lymphoma

A Phase 1/2 Single-center Study Evaluating the Safety and Efficacy of TCR Reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T Cell (ATHENA-2) Therapy in Adults With Refractory/Relapsed B-cell Lymphoma

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Sponsor: Chinese PLA General Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) 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 (SPPL3)-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 (SPPL3) 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 (SPPL3) 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.

Detailed description

Phase 1 (dose escalation) In phase 1, 6-18 subjects will be enrolled. Subjects will receive 3 doses of ATHENA-2 CAR-T cell therapy ( 1× 10\^6 cells/kg, 3× 10\^6 cells/kg, 6 × 10\^6 cells/kg) increases from low dose to high dose according to the "3 + 3" principle: Three (3) subjects are enrolled in a cohort corresponding to a dose level. If 1 subject in a cohort of 3 subjects experiences a dose-limiting toxicity (DLT), 3 additional subjects will be enrolled at the current dose level. For safety purposes, the administration of ATHENA-2 CAR T will be staggered by 28 days between the first two subjects in each cohort. And for each of the remaining cohorts, the administration of ATHENA-2 CAR-T will be staggered by 28 days before enter into the next cohort. Phase 2 (expansion cohort) In phase 2, 10 to 12 subjects will be enrolled and receive ATHENA-2 CAR-T cell infusion at dose of recommended phase 2 dose (RP2D), which will be determined based on the maximum tolerated dose (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 are to evaluate the tolerability and safety of ATHENA-2 CAR-T in patients with r/r B-cell NHL, and determine RP2D. The primary purpose of the phase 2 study is to evaluate the efficacy of ATHENA-2 CAR-T in the above population.

Conditions

• Non-hodgkin Lymphoma

Interventions

Type	Name	Description
BIOLOGICAL	TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T)	Phase 1 dose escalation (3+3): dose 1 (1 × 10\^6 cells/kg), dose 2 (3 × 10\^6 cells/kg), dose 3 (6 × 10\^6 cells/kg); Phase 2: dose of RP2D.
DRUG	Fludarabine	Intravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.
DRUG	Cyclophosphamide	Intravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.

Timeline

• Start date: 2024-04-17
• Primary completion: 2026-04-25
• Completion: 2027-04-25
• First posted: 2024-03-21
• Last updated: 2025-05-25

Locations

3 sites across 1 country: China