Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality.
Mohit SachdevaBrian W BusserSonal TemburniBillal JahangiriAnne-Sophie GautronAlan MaréchalAlexandre JuilleratAlan WilliamsStéphane DepilPhilippe DuchateauLaurent PoirotJulien ValtonPublished in: Nature communications (2019)
Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRACCAR), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRACCAR T cell cytotoxicity and extends survival of tumor-bearing mice. This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner.
Keyphrases
- genome wide identification
- genome wide
- transcription factor
- genome wide analysis
- regulatory t cells
- copy number
- dna methylation
- high resolution
- type diabetes
- anti inflammatory
- climate change
- metabolic syndrome
- risk assessment
- high fat diet induced
- free survival
- immune response
- high density
- mass spectrometry
- brain injury