Diagram of the drug screening platform and the mechanism of miltefosine in CAR-T cells. Credit score: Prof. Wang’s group
A analysis crew led by Prof. Wang Haoyi from the Institute of Zoology (IOZ) of the Chinese language Academy of Sciences has developed a chimeric antigen receptor T (CAR-T) cell exhaustion mannequin and a useful screening platform for figuring out compounds that may rejuvenate exhausted T cells.
Utilizing this progressive platform, the crew recognized the small-molecule compound miltefosine, which considerably enhances the tumor-killing exercise of CAR-T cells. This examine was revealed in Cell Studies Drugs on December 9.
T cell exhaustion is a differentiation state that arises when T cells are uncovered to persistent antigen stimulation. This state is characterised by a progressive lack of effector capabilities, sustained expression of inhibitory receptors, impaired proliferation, and compromised mitochondrial respiration and glycolysis capability.
T cell exhaustion is a important impediment to the efficacy of immune checkpoint blockade (ICB) and CAR-T cell immunotherapies. Manipulating the exhaustion course of might enhance the therapeutic efficacy of T cell responses in most cancers.
To handle this drawback, the researchers generated hypofunctional CAR-T cells by way of a number of rounds of tumor problem and established a drug screening platform utilizing these cells. By screening FDA-approved medication, they found that miltefosine—a small molecule beforehand used to deal with leishmaniasis—might restore the performance of exhausted CAR-T cells. Remarkably, even in a terminally exhausted state the place PD-1 antibody remedy proved ineffective, miltefosine was nonetheless able to boosting CAR-T cell exercise.
Via single-cell RNA sequencing (scRNA-seq) evaluation, the researchers found that miltefosine enhances effector operate, reduces exhaustion, and improves metabolic exercise in hypofunctional CAR-T cells. Additional investigations revealed that miltefosine rescues the glucose uptake deficit and improves glycolytic and oxidative phosphorylation metabolism in a GLUT1-dependent method. These results in the end result in improved efficacy in treating stable tumors.
Furthermore, in each allogeneic and syngeneic tumor fashions, miltefosine considerably enhanced the tumor-clearing capability of CAR-T cells and T cells.
The drug screening platform can assess FDA-approved small molecules utilizing the CAR-T cell exhaustion mannequin. Miltefosine has emerged as a promising candidate for bettering CAR-T cell operate and metabolic exercise, demonstrating the potential for software in immunotherapy.
Extra info:
Xingying Zhang et al, Miltefosine reinvigorates exhausted T cells by focusing on their bioenergetic state, Cell Studies Drugs (2024). DOI: 10.1016/j.xcrm.2024.101869
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Chinese language Academy of Sciences
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Drug screening platform identifies compound for reinvigorating exhausted CAR-T cells (2024, December 13)
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