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Abstract
Background Acute myeloid leukemia (AML) is a complex malignancy developing in the bone marrow leading to challenges in the clinic. In the clinical and preclinical settings, accurate classification of AML patients is essential for the proper model classification which enables researchers to study specific AML subtypes, providing insights into potential mechanisms and therapeutic targets.1 The main limitation in developing effective immunotherapy is due to both, the lack of relevant translational models where immune cells are representative of the actual disease, and the intrinsic AML heterogeneity further complicating the translation of finding into effective immunotherapy. In AML patients, the bone marrow microenvironment induces immunosuppression leading to immune escape therefore impacting our ability to unlock immune cells surveillance.2 Thus, it is key to adopt well characterized preclinical models entirely derived from primary patients’ samples that harbor the autologous immune cells and closely recapitulate the diseased microenvironment.
Methods Champions Oncology has built the largest clinically relevant, engraftable AML models (>50models) bank providing a solution for the unmet need of clinically and biologically relevant models for this complex disease. Every AML primary patient model has been deeply characterized and classified leveraging multiple omics datasets including high complexity flow cytometry, WES, RNAseq, proteomics and phospho-proteomics. We developed the first autologous AML preclinical platform allowing for AML and immune cells ex vivo culture. To capture and analyze the complexity of the interaction between AML and immune cells, we developed a complex flow cytometry panel enabling AML profiling, cancer cell killing and immune phenotype readouts in parallel. While the platform allows for the culture of AML cells together with innate and adaptive immunity players, in this project we particularly focused on T cells.
Results We report that our primary AML models cultured within the AML autologous platform proprietary method present viable and functional autologous immune cells retained in the culture together with leukemic cells throughout the duration of the assay. Leveraging the Autologous AML platform, we observed a correlation between cytotoxic and helper T cell activation and T cell dependent cancer cell killing upon immune stimulation.
Conclusions Knowing that different AML subtypes may respond differently to various treatment modalities we are providing classified, deeply characterized AML primary autologous models to enable successful drug testing in a relevant model system. Moreover, this dataset shows that the model is an ideal system to test for IO drugs in an autologous AML ex vivo context to potentially improve treatments in the future.
References
Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ 2021 Oct 6;375:n2026. doi: 10.1136/bmj.n2026. PMID: 34615640.
Tettamanti S, Pievani A, Biondi A, Dotti G, Serafini M. Catch me if you can: how AML and its niche escape immunotherapy. Leukemia 2022 Jan;36(1):13–22. doi: 10.1038/s41375-021-01350-x. Epub 2021 Jul 23. PMID: 34302116; PMCID: PMC8727297.
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