Myd88 and CD40 Costimulatory Domains for Chimeric Antigen Receptors (SJ-18-0021)

St. Jude Reference #SJ-18-0021

Description

Adoptive cell therapies with T-cells expressing chimeric antigen receptors (CARs) have yet to be as successful for solid tumors as for leukemia, most likely due to factors including suboptimal CAR signaling resulting in limited T-cell activation within the solid tumor microenvironment. To help address this issue, researchers at St. Jude generated an Eph receptor (EphA2) CAR with MyD88.CD40.z endodomains. T-cells transduced with this CAR were much more effective and activated better against EphA2+ than other CAR T-cells. In vivo, they compared the expansion, persistence, and anti-tumor activity of MyD88.CD40.z and 41BB.z CAR T-cells in the EphA2+ LM7 osteosarcoma xenograft model.  MyD88.CD40.z CAR T-cells had greater antitumor activity than 41BB.z CAR T-cells, resulting in a significant survival advantage. In addition, MyD88.CD40.z CAR T-cells expanded more and persisted longer than 41BB CAR T-cells, providing a potential mechanism for their improved anti-tumor activity. Therefore, including MyD88 and CD40 signaling domains in CAR T-cells may improve current CAR T-cell therapy approaches for solid tumors.


 

Keywords

Adoptive cell therapies, T-cell, chimeric antigen receptors (CARs), solid tumors, Eph receptor (EphA2), MyD88.CD40.z, osteosarcoma.


 

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