Intracellular targets as source for cleaner targets for the treatment of solid tumors

• Published in: Biochemical pharmacology Vol. 168; pp. 275 - 284
• Main Authors: Gerber, Hans-Peter, Sibener, Leah V., Lee, Luke J., Gee, Marvin
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.10.2019
• Subjects: ADCs; Antigens; Autologous T cell therapies; CAR-T; TCR-T cells; Antigens; Autologous T cell therapies; CAR-T; ADCs; TCR-T cells
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2019.07.015

Intracellular proteins are degraded by a proteasome into small peptide fragments. These peptides are then transported into the ER lumen by TAP (transporter associated with antigen presentation) where a subset of the peptides are loaded into Class I HLA molecules (pHLA). The loaded pHLA molecules are then transported to the cell surface where they are then presented to the immune system for potential recognition via T cell receptors. [Display omitted] High-potency oncology compounds such as antibody- drug conjugates, T cell redirecting, and CAR-T cell therapies have provided transformational responses in patients with liquid tumors. However, they delivered only limited benefit to solid tumor patients due to the frequent onset of dose limiting toxicities in normal tissues. Such on-target, off-tumor toxicities are caused by recognition of targets present at low-levels on normal tissues. The apparent imbalance between the rapid development of high-potency therapeutic modalities and the slow progress in identification of cleaner targets is illustrated by the fact that most high-potency compounds currently developed in the clinic target cell surface antigens identified over 20 years ago. Therefore, identification of novel, truly tumor-specific targets is critical for the future success of high-potency oncology compounds in solid tumors. One of the most promising approaches to overcome the limitations of targeting cell surface antigens are intracellular targets. The renewed interest in this class of targets is due to the success of immune checkpoint inhibitors, which mediate their anti-tumor responses by activation of cytotoxic T cells recognizing peptide fragments of intracellular targets presented by human leukocyte antigens (HLAs) on the surface of tumor cells. Importantly, many intracellular targets belong to the class of tumor specific antigens (TSAs), which lack presentation on normal tissues. In this report we review the main classes of tumor specific antigens, including viral, neoantigens and shared self-antigens as well as tumor associated antigens (TAAs) and their relevance for therapeutic targeting of solid tumors by high-potency therapeutic modalities.