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Monoclonal antibodies for the treatment of cancer - PubMed

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Review

Monoclonal antibodies for the treatment of cancer

Casey W Shuptrine et al. Semin Cancer Biol. 2012 Feb.

Abstract

Over the past decade, the clinical utility of monoclonal antibodies has been realized and antibodies are now a mainstay for the treatment of cancer. Antibodies have the unique capacity to target and kill tumor cells while simultaneously activating immune effectors to kill tumor cells through the complement cascade or antibody-dependent cellular cytotoxicity (ADCC). This multifaceted mechanism of action combined with target specificity underlies the capacity of antibodies to elicit anti-tumor responses while minimizing the frequency and magnitude of adverse events. This review will focus on mechanisms of action, clinical applications and putative mechanisms of resistance to monoclonal antibody therapy in the context of cancer.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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Figure 1
Figure 1. Proposed mechanisms of resistance to antibody therapy

The most thoroughly characterized mechanism of resistance to antibody therapy is amplification of downstream signaling. In the case of EGFR, resistance to anti-EGFR antibodies can be mediated by mutations (stars) in K-Ras, B-Raf, or PI3K/PTEN that allow tumor cells to bypass receptor activation to activate pro-survival genes (A). Tumor cells may upregulate expression of inhibitory receptors, such as HLA-E and HLA-G, which engage inhibitor receptors on NK cells to inhibit ADCC (B). Similarly, tumor cells may express membrane bound complement regulatory proteins (mCRP), such as CD55 and CD46, which act to inhibit cleavage of C3 by C3 convertase and inhibit generation of the membrane attack complex (MAC) (C). Tumor cells that express MHC I can be recognized by activated CD8+ cytotoxic T lymphocytes (CTL), which release perforin and granzyme to induce tumor cell apoptosis. However, tumor cells often downregulate expression of MHC I and display aberrant antigen processing machinery, resulting in loss of MHC I expression on the cell surface and protection from CTL mediated killing (D). The tumor microenvironment is enriched with myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) that produce IL-10, TGF-β and reactive oxygen species (ROS) to inhibit tumor cell killing by CTL (E).

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