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CARs do present one drawback, in that they can only detect surface-expressed antigens, while natural TCRs can also recognize intracellular antigens. This prevents CARs from targeting antigenic epitopes created by genetic mutations. However, CARs, unlike TCRs, can recognize non-protein epitopes such as carbohydrates and glycolipids.2 In principle, a CAR can be specifically created to target any cell surface molecule.1
For anti-cancer purposes, CARs should ideally target antigens only expressed by cancer cells (e.g., EGFRvIII). Unfortunately, in reality, very few antigens qualify under this criterion, and most CAR targets are antigens expressed at low levels by normal cells (e.g., the breast cancer marker HER2) and/or expressed only by certain cell subsets (e.g., the B-cell markers CD19 and CD20).2 The latter approach will also eliminate healthy cells within that subset, and is thus primarily utilized to treat hematological cancers in situations where replacement therapy is possible.2
1. M. Sadelain, et al., “The basic principles of chimeric antigen receptor design,” Cancer Discov 3(4):388-398, 2013.
2. G. Dotti, et al., “Design and Development of Therapies using Chimeric Antigen Receptor-Expressing T cells,” Immunol Rev 257(1):10, 2014.
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