CAR T-Cells That Recognize Cancer-specific Glycopeptides Across Multiple Cancer Types

SUMMARY

• The development of cancer immunotherapies is limited by a lack of targetable tumor antigens. Most currently targeted antigens have basal expression in healthy tissue, which results in potentially life threatening off-target effects. Moreover, targeting a single antigen alone can lead to the development of therapeutic resistance.
• A COSMC loss-of-function mutation occurs in 1-3% of all cancer cases and results in the truncated glycosylation of serine and threonine amino acid residues in the tumor tissue but not in the surrounding healthy tissue. The investigators isolated an scFv that binds specifically to these truncated glycosylation sites, known as Tn antigens. The scFv is capable of binding to different variants of Tn antigens, and has the potential to recognize a wide breadth of COSMC mutant cancer types. 
• The product is an engineered chimeric antigen receptor (CAR 237) that specifically targets Tn antigens that arise from COSMC loss-of-function mutations. The receptor can recognize several Tn antigens rather than a single antigen, thereby reducing the potential to induce therapeutic resistance.
• In in vivo Jurkat leukemia xenograft mouse models, the investigators demonstrated the capability of T cells transduced with the CAR to eradicate the tumors only carrying the COSMC mutation, but not in wild type COSMC or when wild type COSMC function was restored.

FIGURE

ADVANTAGES

ADVANTAGES

• Targets multiple types of cancer
• Targets multiple antigen variants while remaining tumor specific

APPLICATIONS

• Cancer immunotherapy
• CAR-T therapy  
• BiTE therapy

PUBLICATIONS

• Sharma, P; et al. Structure-guided engineering of the affinity and specificity of CARs against TN-glycopeptides. Proc Natl Acad Sci USA. 2020 June 15.
• Stone, D; et al. A sensitivity scale for targeting T cells with chimeric antigen receptors (CARs) and bispecific T-cell engagers (BiTEs). Oncoimmunology. 2012 Sep 1; 1(6): 863-873.
• Brooks, CL; et al. Antibody recognition of a unique tumor-specific glycopeptide antigen. Proc Natl Acad Sci USA. 2010 Jun 1; 107(22):10056-61.