REVO-U: A next-generation, gene-editing–free universal CAR-T platform to enable ultra–high-yield manufacturing and identification of early clinical activity in relapsed/refractory DLBCL.

Abstract

7013 Background: We previously invented autologous CAR-T product ciltacabtagene autoleucel (Carvykti) for multiple myeloma, with robust efficacy. However, its personalized nature incurs high costs and limits scalability. Conventional universal CAR-Ts rely on complex gene editing, yielding 50-100 doses/batch, yet to be commercially approved. We created REVO-U, a gene-editing-free universal CAR-T platform using proprietary technologies, initiating explorations in hematologic and solid tumors. It enables >3,000 doses/single batch from healthy donor cells, reducing costs and potentially eliminating capacity constraints in cell therapy. Methods: REVO-U uses protein-directed degradation to mitigate GvHD without gene editing. In a single-arm, open-label exploratory study, CD19-targeted REVO-UWD19 was given post-lymphodepletion (fludarabine/cyclophosphamide) with short-term oral mycophenolate sodium (EC-MPS) in relapsed/refractory DLBCL patients. Results: Four subjects treated (see Table for details). Subject 1 (Flu 30/Cy 300 mg/m² + 100e6 cells; EC-MPS 1440 mg BID x5 days, MPA average AUC 22.12 mg·h/L): PK Cmax 4.3k copies/mL, Transient fever (38.5°C, grade 0 CRS); ≥PR ongoing >10 months. Subject 2 (Flu 30/Cy 400 mg/m² + 200e6 cells; EC-MPS 1440 mg BID x11 days, MPA average AUC 71.44 mg·h/L): Cmax 173.9 k copies/mL, grade 1 CRS, CMR by PET-CT (PFS 4 months). Subject 3 (73y, high burden; Flu 30/Cy 500 mg/m² + 200e6 cells; EC-MPS x14 days, MPA average AUC 71.23 mg·h/L): REVO-U CAR-T expansion was highly significant. Cmax reached 19,057.6 k copies/mL, grade 3 CRS/HLH (controlled), followed by prolonged neutropenia and a fatal infection; PR, unconfirmed CR. Subject 4 (post-DLT: Flu 30/Cy 400 mg/m² + 50e6 cells; EC-MPS x22 days, MPA average AUC 15.21 mg·h/L): Cmax 2.01 k copies/mL, No CRS, PD. No GvHD in any patient. The target effective MPA AUC is >30 mg·h/L. Only Subjects 2 and 3 achieved this threshold on average MPA exposure. Conclusions: REVO-U enables ultra-scalable manufacturing like biologic drugs. Early DLBCL data show no GvHD, with expansion, CRS and responses influenced by lymphodepletion, dose & MPA exposure. Timely EC-MPS adjustment per MPA AUC may be needed for efficacy assurance. Promising PK expansion, persistence post-EC-MPS withdrawal, and efficacy signals have also emerged in solid tumor target explorations. We will report updated data on this innovative universal platform across malignancies at future conferences. Clinical trial information: NCT06662227 . Summary of lymphodepletion, cell dosing, MPA exposure, pharmacokinetic, safety, and efficacy. Subject Flu/CTX Dose EC-MPS MPA-mAUC PK Cmax CRS DLT Efficacy PFS # (mg/m 2 (million cells) (Day used) (mg*h/L） (k Copies/mL） (Grade) (30 days) (months) 1 30/300 100 5 22.12 4.3 0 - PR (CR?) >10 2 30/400 200 11 71.44 173.9 1 - CMR 3 3 30/500 200 14 71.23 19057.6 3 + PR (CR?) 4 30/400 50 22 15.21 2.01 0 - PD