A CD38-directed, single-chain T-cell engager targets leukemia stem cells through IFN-γ-induced CD38 expression
Mariam Murtadha1,2, Miso Park3, Yinghui Zhu1,2,4
1Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA.
Blood
|February 23, 2024
Summary
A novel therapy targeting CD38+ acute myeloid leukemia (AML) cells effectively eliminates leukemia stem cells (LSCs) by engaging T cells and inducing interferon gamma (IFN-γ). This approach enhances CD38 expression on resistant LSCs, leading to their destruction without harming healthy cells.
Area of Science:
- Immunology
- Hematology
- Oncology
Background:
- Acute myeloid leukemia (AML) treatment resistance is often due to leukemia stem cells (LSCs) and immune suppression.
- LSCs can be found in CD34+CD38- fractions, posing a therapeutic challenge.
- Interferon gamma (IFN-γ) reduces LSC activity and upregulates CD38 on LSCs.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting LSCs in AML.
- To leverage IFN-γ-induced CD38 expression for immune-mediated LSC elimination.
Main Methods:
- Development of a single-chain CD38-CD3 T-cell engager (BN-CD38).
- Assessment of BN-CD38's ability to engage T cells and AML blasts.
- Evaluation of T-cell activation, expansion, and leukemia cell elimination in vitro and in vivo.
- Analysis of IFN-γ release and its effect on LSC CD38 expression and elimination.
- Testing of BN-CD38's safety on normal hematopoietic stem cells and immune cell development in humanized mice.
Main Results:
- BN-CD38 successfully engaged autologous T cells and CD38+ AML blasts, leading to T-cell activation and leukemia cell elimination.
- BN-CD38 induced IFN-γ release, which upregulated CD38 on CD34+CD38- LSCs, facilitating their elimination.
- BN-CD38 demonstrated significant in vivo efficacy in AML models.
- BN-CD38 did not impair normal hematopoietic stem cell function or immune cell development in humanized mice.
Conclusions:
- BN-CD38 is a promising therapeutic agent for AML, capable of targeting both CD38+ AML blasts and LSCs.
- The combination of T-cell engagement and IFN-γ-mediated CD38 induction offers a novel strategy for eradicating AML LSCs.
- This approach shows potential for safe and effective AML treatment without compromising normal hematopoiesis or immune reconstitution.
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