Editor's Note: Although progress has been made in the treatment of Acute Myeloid Leukemia (AML) over the past few decades, clinical options remain very limited for patients with relapsed/refractory (R/R) disease. Chimeric Antigen Receptor T-cell (CAR-T) therapy has achieved revolutionary breakthroughs in B-cell malignancies; however, its application in the field of AML has faced significant challenges due to limitations in target selection, patient T-cell quality, and potential toxicities (such as long-term bone marrow suppression).At the 2026 European Hematology Association (EHA) Annual Meeting, Professor Martin Wermke from the University Hospital Carl Gustav Carus, TU Dresden, Germany, shared the results of a high-profile first-in-class study—the RevSTAR-123 (AVC-201-01) study. This study evaluated the safety and preliminary efficacy of a “switchable” allogeneic universal CAR-T cell therapy in patients with CD123-positive AML, providing a new paradigm for the precision immunotherapy of AML. The following is a summary of the meeting report organized by Oncology Lookout (Mediamedic).
01 Treatment Background: Challenges of AML Immunotherapy and the Selection of the CD123 Target
The current state of AML treatment is not optimistic, particularly for patients with R/R AML, where response durations to traditional chemotherapy and targeted drugs are limited. Autologous CAR-T therapy faces multiple hurdles in AML: first, after multiple rounds of heavy chemotherapy, the patient’s own T cells are often impaired, making it difficult to expand high-quality CAR-T products; second, finding specific targets is extremely difficult. An ideal target should be highly expressed on leukemia blasts and leukemic stem cells (LSCs) but not on healthy hematopoietic stem cells (HSCs).
CD123 (interleukin-3 receptor alpha chain) is highly expressed in various hematological malignancies, with exceptionally high coverage on AML blasts and LSCs, making it a target with great potential. However, because CD123 is also expressed to some extent on normal hematopoietic progenitor cells, use of traditional long-acting CAR-T therapy may lead to irreversible long-term bone marrow aplasia. To resolve this contradiction, the RevSTAR-123 study introduced a “switchable” mechanism and an “allogeneic universal” design.
02 Technical Core: The “Switchable” Mechanism and Genetic Modification of the RevCAR System
The RevCAR system is an innovative second-generation CAR-T design, the core logic of which lies in separating the recognition component from the effector component. • Inert RevCAR-T Cells: These T cells express a CAR that does not directly recognize any natural antigen in the body but instead carries a universal adapter peptide. Without the “Targeting Module (RTM),” RevCAR-T cells remain in an inactive state within the body. • Targeting Module (RTM-123): This is a bispecific antibody molecule. One end recognizes the adapter peptide on the RevCAR-T cell, while the other end recognizes the CD123 antigen on the surface of AML cells. • “Switch” Logic: The RTM-123 molecule is small and has an extremely short half-life in the body, thus requiring maintenance of system activity through continuous 24-hour intravenous infusion. Once the RTM infusion is stopped, the connection between CAR-T cells and tumor cells is severed, and their killing activity rapidly disappears. This design provides a “safety switch” for managing severe cytokine release syndrome (CRS) or bone marrow suppression in clinical settings.
Additionally, to achieve “allogeneic universal” application, the research team utilized CRISPR/Cas9 technology to perform precise genome editing on T cells derived from healthy donors:
- Knockout of the TCR locus: To prevent graft-versus-host disease (GVHD).
- Knockout of the MHC class II molecule locus: To prevent immune rejection by host CD4+ T cells.
- Selective removal of HLA-A molecules: To prevent attacks from host CD8+ T cells and NK cells, while retaining some HLA molecules to maintain cell survival in vivo.
03 Clinical Study Design: Progress of the REVSTAR-123 Phase
REVSTAR-123 is a Phase Ia dose-escalation study. Key inclusion criteria included: relapsed or refractory AML, or MRD (measurable residual disease)-positive AML lacking standard treatment options; CD123 expression rate on leukemia blasts ≥20%; adequate organ function; and matching of the patient’s HLA phenotype with the donor T-cell batch.
Dosing Regimen: After receiving standard lymphodepletion chemotherapy (fludarabine + cyclophosphamide for 3 days), patients received a single dose of RevCAR-T cells on Day 1, while simultaneously beginning a continuous 24-hour intravenous infusion of RTM-123. The first infusion cycle lasted 21 days. For patients achieving clinical benefit, repeated re-stimulation cycles were allowed (12 days of RTM infusion per cycle).
As of the data analysis date, a total of 17 patients were enrolled. The median age was 63 years, the median number of prior treatment lines was 4, and 65% of patients had received at least one prior allogeneic hematopoietic stem cell transplant.
04 Safety Evaluation: Clinical Validation of the “Safety Switch”
Safety was the primary endpoint of this study. The data indicated that the overall safety profile of the RevCAR system is favorable and manageable: • CRS Status: CRS was observed but was low-grade (Grade 1-2) in the majority of patients. • Neurotoxicity (ICANS) and GVHD: No ICANS of any grade was observed in the entire group, nor did GVHD occur. • Dose-Limiting Toxicity (DLT): Only one case of immune effector cell-associated hemophagocytic syndrome (IEC-HS) secondary to macrophage activation syndrome was observed at the highest dose level. This case was successfully managed using Anakinra, dexamethasone, and immediately turning off the “switch” (stopping RTM infusion).
Typical Case of “Switch” Function (43-year-old male patient):
This patient had relapsed after two prior allogeneic transplants and received RevCAR-T treatment upon enrollment. Within 24 hours after starting the RTM infusion, the patient developed Grade 2 CRS with a sharp rise in serum IL-6 levels. Clinicians chose to stop the RTM infusion, after which a rapid decline in serum RTM levels was observed, followed by a decrease in IL-6, and CRS symptoms resolved completely within a short period. Subsequently, clinical attempts were made to restart the RTM infusion; the patient again developed Grade 2 CRS, which resolved quickly once the infusion was stopped again. This process clearly demonstrated the high controllability and safety of the RevCAR system in the human body.
05 Kinetics and Efficacy: Extraordinary Performance of Allogeneic CAR-T
Despite being derived from allogeneic sources, the in vivo kinetics of RevCAR-T exceeded expectations: • Expansion and Persistence: At dose level 15 (DL15), the median peak expansion level of RevCAR-T exceeded 160,000 copies/μg DNA. In the DL15 group, 5 out of 8 patients showed cell persistence of more than 30 days, with a median persistence of 45 days for the entire group. This data is significantly superior to that reported for many previous universal CAR-T products and even comparable to some autologous CAR-Ts. • Preliminary Efficacy: Among the 12 evaluable patients, 4 objective responses were observed. In the higher dose level groups, responses were more significant, including 3 cases of complete remission/complete remission with incomplete hematologic recovery (CR/CRh), 2 of which converted to MRD-negativity. Additionally, there was 1 case of morphologic leukemia-free state (MLFS) and 1 case of conversion from MRD-positivity to MRD-negativity. In some patients, remission was maintained long-term after receiving multiple rounds of RTM re-stimulation.
06 Conclusion and Outlook
Professor Martin Wermke concluded that the RevSTAR-123 study successfully validated the feasibility of the first-in-class switchable, allogeneic universal CAR-T cells in the treatment of CD123+ AML. This system not only overcomes the issue of insufficient autologous T-cell quality through its allogeneic design but also achieves precise regulation of cell activity through the unique “RTM switch” mechanism, effectively balancing anti-tumor potency with potential off-target toxicities (such as bone marrow suppression).
Based on the positive data from the Phase Ia study, the trial has entered the Phase Ib dose-expansion phase, which will continue to enroll 20 additional R/R AML patients at the DL15 dose level. The successful translation of this innovative technology not only brings new hope to AML patients but also provides a technical foundation for future multi-target combination therapies and regulation of more complex immune microenvironments.
