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Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML
Fabiana Perna1, Samuel H Berman1, Rajesh K Soni2
1Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34+CD38- hematopoietic cells, T cells, or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.
Insights
Chimeric antigen receptor (CAR) therapy shows promise for acute myeloid leukemia (AML). Researchers identified potential targets by analyzing leukemia and normal cell data, developing a combinatorial strategy for safer and more effective CAR treatments.
Area of Science:
- Immunotherapy
- Hematologic Malignancies
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) therapy targeting CD19 has revolutionized acute lymphoblastic leukemia (ALL) treatment.
- Identifying effective and safe CAR targets for acute myeloid leukemia (AML) remains a significant challenge.
- The AML surfaceome requires thorough investigation for suitable CAR targets with minimal off-tumor toxicity.
Purpose of the Study:
- To identify novel cell surface targets for CAR therapy in acute myeloid leukemia (AML).
- To develop a robust strategy for selecting CAR targets with high efficacy and safety profiles in AML.
- To explore combinatorial targeting approaches for overcoming challenges in AML CAR therapy.
Main Methods:
- Integrated analysis of large-scale transcriptomics and proteomics datasets from AML and normal tissues.
- Development of a computational algorithm to identify targets expressed on leukemia stem cells but absent in critical normal cell populations (hematopoietic stem cells, T cells) and vital tissues.
- Design and evaluation of a generalizable combinatorial targeting strategy based on stringent efficacy and safety criteria.
Main Results:
- Initial investigations did not identify single AML surface targets with a safety and efficacy profile comparable to CD19 in ALL.
- A combinatorial targeting strategy was developed, fulfilling rigorous criteria for both effectiveness and systemic safety.
- Several promising target pairings were identified for future development in AML CAR therapy.
Conclusions:
- Direct single-target CAR therapy for AML faces significant hurdles due to target expression profiles.
- Combinatorial targeting offers a viable and promising strategy to enhance the safety and efficacy of CAR therapy for AML.
- Further research into identified target pairings is warranted to advance CAR-based treatments for acute myeloid leukemia.
