Improving Brain Tumor Targeted Antigen Receptor T Cell Function

City of Hope, Duarte, CA

Chimeric Antigen Receptor (CAR) T cells, recently approved by the FDA, have revolutionized leukemia treatment. However, CAR T cell solid tumor therapy has been disappointing, because myriad inputs contribute to make solid tumors resistant to immune attack. Indeed, despite our very encouraging initial clinical results using IL13Ra2-targeted CAR T cells in glioblastoma multiforme, the benefit is only temporary; CAR T cells vanish from patients within 7 days of administration, and rapidly lose the ability to kill brain tumor cells in culture. Improving CAR T cell persistence will vastly improve their efficacy in treating brain tumors.

Doing this requires us to understand and manipulate protein-level events in CAR T cells, as proteins are the ultimate effectors of cellular function. Identifying proteins responsible for T cell persistence will be critical to keeping CAR T cells from disappearing. The best way to do that is with protein-focused techniques like mass spectrometry and mass cytometry.

I pioneered a groundbreaking technique for using mass spectrometry on small numbers of cells, which has not been possible before. We will use this and other protein-focused techniques, as well as biological models of brain tumors and the immune system, to identify a unique protein signature corresponding to T cell survival and persistence. We hypothesize that these activated protein circuits can be leveraged to improve CAR T cell persistence and efficacy.