Researchers at St. Jude have developed a set of markers for identifying the best CD8+ T-cells for immunotherapy, and thus ways to overcome T cell exhaustion.
The invention can be used to assess the functional potential of host tumor or viral-specific CD8 T cells prior to administration of therapeutics that seek to directly expand endogenous T cells; and can be used as a biomarker to track the differentiation status of CD8 T cells in patients that receive chemotherapeutic agents that target epigenetic modifications such as the use of 5-azacytidine.
T-cell activity can also be modulated by altering DNA methylation status which can prevent T-cell exhaustion and maintain effector functions during sustained antigen exposure to treat symptoms of chronic infections and cancer. Further, the memory cell methylation markers can further be used to identify subjects with chronic infections or cancer that would benefit from personalized therapy, including immune checkpoint blockade therapy.
The invention can be used as a biomarker to assess the poised effector potential (functional state) of CD8 T cells that have undergone in vitro differentiation, such as occurs during the development of CAR T cell products prior to infusion, without the need for additional in vitro stimulation. Current in vitro stimulation assays require a large amount of cellular material as well as prior knowledge of the kinetics for transcriptional up-regulation in the corresponding population of cells. Our invention can be performed with a very low number of cells (~500) and does not require prior knowledge of the kinetics for transcriptional up-regulation. The biomarker analyses is not the same as the Dnmt3a deletion for engineering T cells, the Dnmt3a exhaustion-associated DNA methylation programs can also serve as biomarker.
Gene therapy, immunotherapy, t-cell exhaustion, DNA methylation, chronic infection, cancer
Granted Patents or Published Applications
Related Scientific References
Akondy et al., “Origin and differentiation of human memory CD8 T cells after vaccination.” Nature, 13 December 2017. doi:10.1038/nature24633
A more general news article describing the Nature publication further can be found at https://www.eurekalert.org/pub_releases/2017-12/sjcr-mtc121317.php
Ghoneim et al., “De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.” Cell, Volume 170, Issue 1, 29 June 2017. DOI: http://dx.doi.org/10.1016/j.cell.2017.06.007
A more general news article describing the Cell publication further can be found here: http://www.genengnews.com/gen-news-highlights/epigenetic-reprogramming-may-boost-immunotherapy/81254578
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