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Preclinical Evaluation of CD64 As a Potential Target For CAR-T-cell Therapy For Acute Myeloid Leukemia
Xiaolei Sun1, Guoling Wang1, Shiyu Zuo1
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin.
Abstract:
The relapsed and refractory acute myeloid leukemia (AML) patients receiving traditional chemotherapies have poor survival rate. Chimeric antigen receptor (CAR)-modified T cells have demonstrated remarkable effectiveness against some malignancies. However, most of CAR-Ts targeting the candidate proteins on AML cells induce hematopoietic cell suppression. Because of extensive heterogeneity among different types of AML, it is essential to expand the choice of target antigen for the CAR-T treatment of AML. CD64 (FcγRI) is a transmembrane protein with broad expression on various types of AML cells, especially monocytic AML cells, but it is absent on hematopoietic stem cells (HSCs) and most of nonmonocytes. Here, we found that some types of AML patients showed the homogeneous high-level expression of CD64. So, we created a CAR-T targeting CD64 (64bbz) and further verified its high efficiency for eradicating CD64+AML cells. In addition, 64bbz showed no cytotoxicity to HSCs. Overall, we developed a new treatment option for AML by using CD64 CAR-T cells while avoiding ablation of HSCs.
Insights
Chimeric antigen receptor (CAR)-T therapy shows promise for acute myeloid leukemia (AML). Researchers developed a CD64-targeting CAR-T (64bbz) effective against AML cells while sparing hematopoietic stem cells.
Area of Science:
- Oncology
- Immunotherapy
- Hematology
Background:
- Relapsed/refractory acute myeloid leukemia (AML) patients have poor outcomes with chemotherapy.
- Chimeric antigen receptor (CAR)-T cell therapy is effective but faces challenges with AML heterogeneity and target antigen selection.
- Current CAR-T approaches targeting AML can cause harmful hematopoietic cell suppression.
Purpose of the Study:
- To identify a novel target antigen for CAR-T therapy in AML that avoids hematopoietic stem cell (HSC) toxicity.
- To develop and validate a CD64-targeting CAR-T (64bbz) for AML treatment.
Main Methods:
- Identified CD64 (FcγRI) as a potential target due to its expression on AML cells and absence on HSCs.
- Engineered a CD64-specific CAR-T construct (64bbz).
- Evaluated the efficacy and safety of 64bbz CAR-T cells against CD64-expressing AML cells and HSCs in vitro.
Main Results:
- CD64 is homogeneously expressed at high levels on certain AML patient samples.
- The 64bbz CAR-T demonstrated high efficiency in eradicating CD64+ AML cells.
- 64bbz CAR-T cells showed no significant cytotoxicity towards hematopoietic stem cells.
Conclusions:
- CD64 is a viable and specific target antigen for CAR-T therapy in AML.
- CD64-targeting CAR-T cells (64bbz) offer a promising new therapeutic strategy for AML.
- This approach provides an effective AML treatment option while preserving HSCs, potentially improving patient survival and reducing treatment-related toxicities.
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