| 英文摘要: | Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults and is responsible for more than 10,000 deaths annually in the United States. Immunotherapy has revolutionized the treatment of cancers. T-cell based therapy involving the infusion of genetically modified cells has the potential to deliver long-lasting remissions, eventually leading to cures. Despite this promise, treatments remain unpredictable, so newer methods are required to assist the biomanufacturing of immune cells with defined properties. This research project aims to deliver on data-driven engineering methods to rapidly engineer the potency of T cells for the treatment of AML and to test these in mice. Additionally, students at all levels will be trained through the development and delivery of animation-based tutorials and interactive games that teach immunotherapy, cell metabolism, T-cell function, and cellular responses to cancer. The educational outreach is also advancing student engagement in immunotherapy through research experiences for K-12, undergraduate and graduate students.
Adoptive cell therapy (ACT) based on the transfer of chimeric antigen receptor (CAR) T cells has demonstrated significant anti-tumor effects in patients with refractory B-cell malignancies. The remarkable clinical success of CAR+ T cells has spurred the development of this approach for other leukemias and solid tumors. In spite of the clinical potential of ACT, its efficacy remains unpredictable, and newer approaches are required to define the key components of the efficacy of CAR+ T cells. The incomplete understanding of the role of metabolism in the anti-tumor efficacy of cells has severely limited the biomanufacturing T cells with predictable potency, and this is a fundamental limitation. The objective of this research project is to quantify the dynamic metabolic profile, the complete transcriptome, and the functional competency of CAR+ T cells targeting the sialoadhesin receptor 3 (CD33), at single-cell resolution, and to determine if directly altering T-cell metabolism provides new avenues to immunotherapeutic treatment or treatment enhancement. A suite of innovative high-throughput single-cell methodologies that have been developed and implemented, including real-time metabolic profiling, Timelapse Imaging Microscopy in Nanowell Grids (TIMING), and single-cell RNA-seq, are being utilized. The ability of these engineered CAR+ T-cell populations to control the growth of human tumors is being tested in immunodeficient mice. This work will establish the heterogeneity and correlation between fundamental T-cell processes like metabolism, function, and phenotype, and thus will have a broad impact on T-cell immunology. |