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Nik Sgourakis and CHOP colleagues publish research on PC-CAR protein structure in Science Immunology

May 14, 2024

Nik Sgourakis and CHOP colleagues publish research on PC-CAR protein structure in Science Immunology

May 14, 2024
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NexTGen researchers, Dr. Nikolaos Sgourakis and Dr. John Maris, working with a team out of The Children’s Hospital of Philadelphia (CHOP) published a paper in December 2023 in the journal Science Immunology entitled “Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion.” 

 

As part of NexTGen, The CHOP team’s mission is to find ways to engineer tumor-specific CAR T cells to mitigate risk of toxicities to patients. One hurdle they face, is that many tumor antigens are expressed intracellularly. This means that the antigens are present on the inside of a tumor cell instead of on the cell surface. CARs can only recognize and attach to antigens on the surface of tumor cells. To overcome this, the team developed peptide-centric CARs (PC-CAR), which can recognize the intracellular antigens after they have been degraded into peptides and presented on the cell surface. This naturally occurring process of breaking down antigens into smaller pieces (peptides) and moving them to the cell’s surface allows for the immune system (or PC -CARs in this case) to find and respond to abnormal or infected cells.

 

The CHOP team characterized a PC-CAR called 10LH (named for its amino acid structure) that’s designed to target a peptide derived from PHOX2B. PHOX2B is an oncoprotein that is that is abundant in neuroblastoma. They found that the method the PC-CARs use to attach to cancer cells and the way it interacts with the peptide is common in many people. This makes it potentially effective for a large patient population. In the paper, the team highlights how PC-CARs have significant advantages over traditional TCR immunotherapies such as lack of off-target toxicities

 

The findings in this paper will help NexTGen create a CAR T cell therapy that targets solid tumor cells more effectively while avoiding harming healthy cells. From a patient perspective, this is a key aspect of developing new therapies to treat children. 

 

Key terms

Antigen: A molecule, like a protein or carbohydrate, that is recognized by the immune system and can trigger an immune response.

PC-CAR: T cells engineered with peptide-centric chimeric antigen receptors. 

Peptide: A short chain of ammino acids that are smaller than proteins. They serve as signaling molecules, hormones, and components of cell structures. 

Oncoprotein: A protein that plays a significant role in the development and progression of cancer through various biological mechanisms. 

TCR: T cell receptor 

Off-target toxicities: adverse side effects of a drug that occur due to its interaction with a biological target other than the intended target.

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