He et al. generated CAR T cells (237CART) with the binding domain of the 237 antibody (237Ab) which recognizes an aberrantly O-glycosylated murine podoplanin (Tn-PDPN). In a mouse leukemia model, Tn-PDPN-expressing Jurkat cells were eradicated by 237CART cells. Unexpectedly, native Jurkat cells also were eradicated. In vitro, native Jurkat cells and other COSMC- cells that didn’t bind 237Ab but expressed Tn-MUC1 or other Tn-glycosylated proteins were lysed by 237CART cells. Reactivity with multiple Tn-glycosylated proteins (expressed only on cancer cells) identify 237CART cells as a promising candidate to treat Tn-expressing tumors.
Contributed by Samuel Goldman
Human cancer cells were eradicated by adoptive transfer of T cells transduced with a chimeric antigen receptor (CAR) made from an antibody (237Ab) that is highly specific for the murine Tn-glycosylated podoplanin (Tn-PDPN). The objectives were to determine the specificity of these CAR-transduced T (CART) cells and the mechanism for the absence of relapse. We show that although the 237Ab bound only to cell lines expressing murine Tn-PDPN, the 237Ab-derived 237CART cells lysed multiple different human and murine cancers not predicted by the 237Ab binding. Nevertheless, the 237CART cell reactivities remained cancer specific because all recognitions were dependent on the Tn glycosylation that resulted from COSMC mutations that were not present in normal tissues. While Tn was required for the recognition by 237CART, Tn alone was not sufficient for 237CART cell activation. Activation of 237CART cells required peptide backbone recognition but tolerated substitutions of up to 5 of the 7 amino acid residues in the motif recognized by 237Ab. Together, these findings demonstrate what we believe is a new principle whereby simultaneous recognition of multiple independent Tn-glycopeptide antigens on a cancer cell makes tumor escape due to antigen loss unlikely.
Author Info: (1) Committee on Cancer Biology, and. (2) Department of Pathology, The University of Chicago, Chicago, Illinois, USA. (3) Department of Pathology, The University of Chicago, Chicag
Author Info: (1) Committee on Cancer Biology, and. (2) Department of Pathology, The University of Chicago, Chicago, Illinois, USA. (3) Department of Pathology, The University of Chicago, Chicago, Illinois, USA. (4) Department of Pathology, The University of Chicago, Chicago, Illinois, USA. (5) Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark. (6) Department of Pathology, The University of Chicago, Chicago, Illinois, USA. (7) Department of Pathology, The University of Chicago, Chicago, Illinois, USA. (8) Department of Biochemistry, University of Illinois, Urbana, Illinois, USA. (9) Biooncology Consultants, San Diego, California, USA. (10) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Center for Cellular Therapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. (11) Center for Cellular Therapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. (12) Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark. (13) Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark. (14) Institute of Immunology, Charite - Universitatsmedizin Berlin, Campus Buch, Berlin, Germany. (15) Department of Pathology, The University of Chicago, Chicago, Illinois, USA. (16) Department of Biochemistry, University of Illinois, Urbana, Illinois, USA. (17) Committee on Cancer Biology, and. Department of Pathology, The University of Chicago, Chicago, Illinois, USA. Committee on Immunology, The University of Chicago, Chicago, Illinois, USA.
