Project

Study of inducible glycome manipulation of CAR-T cells upon antigen exposure in the tumor environment

Duration
01 November 2020 → Ongoing
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Engineering and technology
    • Cell, tissue and organ engineering
    • Cellular therapy
    • Gene and molecular therapy
    • Medical molecular engineering of nucleic acids and proteins
Keywords
glyco-engineering Glycosylation Immunotherapy Inducible gene expression (knockout/overexpression)
 
Project description

Glycosylation is the modification of macromolecules with carbohydrate structures. These carbohydrate structures together make up a layer at the outside of all of our cells, which we call the glycocalyx, or cell surface glycome. This forest of carbohydrate structures is the first thing that a molecule or cell senses when approaching a mammalian cell. Recently, we have developed the necessary technology for Chimeric Antigen Receptor (CAR) overexpression and CRISPR-Cas9 engineering of T cells for the introduction of specific changes in their cell surface glycome. There is strong evidence that such glycome manipulations could have a great impact on the functionality of these cells, as cytotoxic T cells with changed glycotypes are less sensitive to certain activity-suppressing sugar-binding proteins (lectins) that are produced by tumors and other inflamed tissues. This project takes this glyco-engineering to a next level by encompassing the design and implementation of inducible glycome manipulation of CAR-T cells upon antigen exposure in the tumor environment. This allows us to study altered glycosylation variants that would affect early events upon T cell adoptive transfer in the blood stream if they were engineered constitutively. In parallel we would like to test the possibility of in vivo delivery of the CAR genes and inducible glycosylation engineering cassette directly and selectively to human cytotoxic T cells, making tedious ex vivo manipulations of lymphocytes obsolete.