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Review
. 2022 Sep 14:12:892212.
doi: 10.3389/fonc.2022.892212. eCollection 2022.

Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling

Gabriele Hintzen  1 , Holger J Dulat  1 , Erich Rajkovic  1
Affiliations
Review

Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling

Gabriele Hintzen et al. Front Oncol. .

Abstract

The epidermal growth factor receptor (EGFR) is a key player in the normal tissue physiology and the pathology of cancer. Therapeutic approaches have now been developed to target oncogenic genetic aberrations of EGFR, found in a subset of tumors, and to take advantage of overexpression of EGFR in tumors. The development of small-molecule inhibitors and anti-EGFR antibodies targeting EGFR activation have resulted in effective but limited treatment options for patients with mutated or wild-type EGFR-expressing cancers, while therapeutic approaches that deploy effectors of the adaptive or innate immune system are still undergoing development. This review discusses EGFR-targeting therapies acting through distinct molecular mechanisms to destroy EGFR-expressing cancer cells. The focus is on the successes and limitations of therapies targeting the activation of EGFR versus those that exploit the cytotoxic T cells and innate immune cells to target EGFR-expressing cancer cells. Moreover, we discuss alternative approaches that may have the potential to overcome limitations of current therapies; in particular the innate cell engagers are discussed. Furthermore, this review highlights the potential to combine innate cell engagers with immunotherapies, to maximize their effectiveness, or with unspecific cell therapies, to convert them into tumor-specific agents.

Keywords: CAR-T therapy; adaptive immunity; bispecific antibody; cancer; epidermal growth factor receptor; innate cell engager; innate immunity; tyrosine kinase inhibitor.

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Conflict of interest statement

All authors are employees of Affimed GmbH. The authors declare that this study received funding from Affimed GmbH. The funder had the following involvement with the study: funded the writing assistance.

Figures

Figure 1
Figure 1
EGFR-targeting therapies inhibiting EGFR activation and signal transduction. (A) EGFR signaling induced by specific ligands, including EGF and TGFα among others, starts with the conformational switch upon binding of a ligand to the EGFR extracellular domain, the dimerization of EGFR monomers and transphosphorylation of intracellular tyrosine kinase domains, which creates docking sites for the adaptor molecules, leading to the activation of key downstream signaling pathways that govern cell proliferation and growth. Certain mutations in the EGFR kinase or extracellular domain induce a constitutively active state and ligand-independent oncogenic signaling downstream of activated EGFR, thus causing uncontrolled tumor cell proliferation and growth. (B) Currently approved therapeutic agents for the treatment of patients with lung or colorectal cancer, or SCCHN include TKIs targeting the EGFR kinase activity (e.g., first-generation small-molecule EGFR kinase inhibitors gefitinib, erlotinib and icotinib), which show particularly high efficacy in the presence of activating EGFR kinase domain mutations, and anti-EGFR antibodies (e.g., cetuximab) that prevent binding of a ligand to the wild-type EGFR and the activation of EGFR and the downstream signaling cascades. Other therapeutic approaches take advantage of individual signaling components downstream of EGFR to disrupt the EGFR signaling cascades and impair tumor cell proliferation and growth. EGF, epidermal growth factor; EGFR, EGF receptor; SCCHN, squamous cell carcinoma of the head and neck; TGFα, transforming growth factor α; TKIs, tyrosine kinase inhibitors.
Figure 2
Figure 2
The mechanisms of ADCC and ADCP response. Monoclonal therapeutic antibodies designed to target specific tumor cell antigens can also use their Fc portion of the immunoglobulin to anchor NK cells and macrophages through specific Fc receptors expressed on the surface of these cells. Such interactions trigger activating signals downstream of Fc receptors in NK cells and macrophages and lead to NK cell-mediated ADCC and macrophage-mediated ADCP responses. NK cells brought in the vicinity of target tumor cells by monoclonal antibodies kill those cells predominantly through the perforin/granzyme cell death pathway, while activated macrophages engulf antibody-opsonized target tumor cells and degrade them through acidification of the phagosome. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; Fc, fragment crystallizable; NK, natural killer.
Figure 3
Figure 3
Mechanism of action of an innate cell engager targeting EGFR and CD16A. AFM24, a fully human tetravalent bispecific innate cell engager, binds simultaneously the CD16A receptor on NK cells or macrophages, with a much higher affinity than monoclonal antibodies, and the EGFR antigen on the surface of tumor cells. This creates a bridge between innate immune cells and EGFR-expressing tumor cells enabling ADCC mediated by NK cells and ADCP mediated by macrophages. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; EGFR, epidermal growth factor receptor; ICE, innate cell engager; NK, natural killer.
Figure 4
Figure 4
AFM24 activity is independent of EGFR signaling function. AFM24-mediated killing of EGFR-expressing tumor cells, by inducing ADCC and ADCP responses, does not rely on the EGFR activity, its mutational status or the disruption of downstream signaling pathways. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; EGFR, epidermal growth factor receptor.
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