Antibody-based immunotherapy of cancer

Abstract

By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. We discuss these innovative strategies and propose how they will impact the future of antibody-based cancer therapy.

Figure 1. Mechanisms of action of antibody immunotherapy in cancer

Mechanisms of action of antibodies in cancer therapy are diverse and represent the versatility of antibody-based approaches. Here, four different strategies are depicted. Upper left: direct cytotoxicity, in which mAbs can induce direct cytotoxicity in tumor cells by perturbing oncogenic signaling pathways or where immunoconjugates can carry cytotoxic agents to targeted cells. Lower left: FcR-mediated immune effector engagement, in which the Fc portion of mAbs can engage immune effector cells including soluble complement-mediated cytotoxicity (CMC, through the membrane attack complex, MAC) as well as NK cells, macrophages and dendritic cells through FcRs, allowing for antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and immune complex (IC) uptake. Upper right: Non-restricted activation of cytotoxic T cells, in which tumor infiltrating cytotoxic T lymphocytes (CTLs) can be activated against tumor cells–independent of T cell receptor (TCR) specificity–by engaging co-receptors on the T cells and tumor antigens. Lower right: blockade of inhibitory signaling, in which cytotoxic lymphocytes, including NK cells and CTLs, express inhibitory receptors for various ligands that may be expressed by tumor cells. Antagonistic antibodies that target these inhibitory receptors can block ligand-receptor interactions so that targeted cytotoxicity can ensue. These four strategies enhance tumor cell death, which can promote phagocytosis of tumor cell antigens, and induction of adaptive immune responses (bottom right) in two ways: MHC class I cross presentation and priming of cytotoxic T cells and MHC class II presentation and priming of helper T cells. These adaptive immune responses can lead to enhanced–and possibly persistent–anti-tumor immunity.