Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells
Laura Volta1,2, Renier Myburgh2, Christian Pellegrino1,2
1Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
Abstract:
CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.
Insights
This study introduces adaptor-CAR (AdFITC-CAR) T-cells for targeting acute myeloid leukemia (AML). This adaptable platform enhances AML cell targeting and offers potential for safer, more effective cancer immunotherapy.
Area of Science:
- Immunotherapy
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is approved for B- and plasma-cell malignancies but faces limitations in efficacy and safety.
- Targeting heterogeneous cancers like acute myeloid leukemia (AML) requires versatile antigen targeting and controllable effector activity.
- Current CAR T-cell therapies can eliminate healthy cells and lack on-off switching, necessitating strategies for safer application in AML.
Purpose of the Study:
- To develop an adaptable CAR T-cell platform for targeting acute myeloid leukemia (AML).
- To enable versatile antigen targeting and conditional activity modulation for improved AML immunotherapy.
- To investigate the efficacy of adaptor-CAR (AdFITC-CAR) T-cells in preclinical AML models.
Main Methods:
- Development of adaptor-CAR (AdFITC-CAR) T-cells utilizing fluoresceinated antigen-binding diabody adaptors.
- In vitro assessment of AdFITC-CAR T-cell efficacy in lysing AML cells, including combinatorial adaptor use.
- In vivo evaluation of AdFITC-CAR T-cells in xenogeneic mouse models of AML, comparing single and combinatorial adaptor strategies.
Main Results:
- AdFITC-CAR T-cells demonstrated enhanced lysis of AML cells in vitro when using combined adaptors.
- In vivo, AdFITC-CAR T-cells with single adaptors showed efficacy comparable to direct CAR T-cells.
- Combinatorial use of adaptors with AdFITC-CAR T-cells significantly improved therapeutic efficacy against AML cell lines and primary AML in mouse models.
Conclusions:
- AdFITC-CAR T-cells provide a proof-of-concept for adaptable and enhanced immune targeting of AML.
- The platform allows for matching adaptors to specific AML antigen profiles and modulating activity.
- Combinations of adaptors can overcome limitations of single-target CAR T-cell therapies, offering improved efficacy and safety potential for AML treatment.
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