NCT06323525

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

Recruiting now Phase 1, PHASE2 Last updated 25 May 2025

What this trial tests

Phase 1, PHASE2 trial testing TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T) in Non-hodgkin Lymphoma in 30 participants. Currently enrolling.

Timeline

17 April 2024

Primary endpoint
25 April 2026

25 April 2027

Quick facts

Lead sponsor	Chinese PLA General Hospital
Phase	Phase 1, PHASE2
Status	Recruiting now
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	30
Start date	17 April 2024
Primary completion	25 April 2026
Estimated completion	25 April 2027
Sites	3 locations across China

Drugs / interventions tested

• TCR reserved and Power3 (SPPL3) gene knock-out allogeneic CD19-targeting CAR-T cell (ATHENA-2 CAR-T)
• Fludarabine (FLUDARABINE) — full drug profile →
• Cyclophosphamide (cyclophosphamide) — full drug profile →

Conditions studied

• Non-hodgkin Lymphoma — all drugs for Non-hodgkin Lymphoma →

Sponsor

Chinese PLA General Hospital

Who can join

Adults 18 to 70, any sex, with Non-hodgkin Lymphoma. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

4 peer-reviewed publications reference this trial (live from Europe PMC):

1. Insights into next-generation immunotherapy designs and tools: molecular mechanisms and therapeutic prospects.
   Qin H, Zhou Z, Shi R, Mai Y, et al · · 2025 · cited 15× · PMID 40483473 · DOI 10.1186/s13045-025-01701-6
2. Allogeneic CAR-engineered cellular therapy for relapsed and refractory large B cell lymphoma: a systematic review and meta-analysis.
   Biederstädt A, Bassermann F, Hecker JS. · · 2025 · cited 6× · PMID 40698082 · DOI 10.3389/fimmu.2025.1585556
3. Mechanisms of Resistance to CAR T-Cells and How to Overcome Them.
   Legato L, Bisio M, Fasano F, Benevolo Savelli C, et al · · 2025 · cited 3× · PMID 40981226 · DOI 10.3390/mps8050108
4. Generating advanced CAR-based therapy for hematological malignancies in clinical practice: targets to cell sources to combinational strategies.
   Zhou S, Yang Y, Jing Y, Zhu X. · · 2024 · cited 3× · PMID 39372412 · DOI 10.3389/fimmu.2024.1435635