Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation

Abstract

Immunoglobulin (Ig) G1 antibodies stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab, an IgG1 isotype monoclonal antibody, is a standard-of-care treatment for locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and metastatic colorectal cancer (CRC). Here we review evidence regarding the clinical relevance of cetuximab-mediated ADCC and other immune functions and provide a biological rationale concerning why this property positions cetuximab as an ideal partner for immune checkpoint inhibitors (ICIs) and other emerging immunotherapies. We performed a nonsystematic review of available preclinical and clinical data involving cetuximab-mediated immune activity and combination approaches of cetuximab with other immunotherapies, including ICIs, in SCCHN and CRC. Indeed, cetuximab mediates ADCC activity in the intratumoral space and primes adaptive and innate cellular immunity. However, counterregulatory mechanisms may lead to immunosuppressive feedback loops. Accordingly, there is a strong rationale for combining ICIs with cetuximab for the treatment of advanced tumors, as targeting CTLA-4, PD-1, and PD-L1 can ostensibly overcome these immunosuppressive counter-mechanisms in the tumor microenvironment. Moreover, combining ICIs (or other immunotherapies) with cetuximab is a promising strategy for boosting immune response and enhancing response rates and durability of response. Cetuximab immune activity-including, but not limited to, ADCC-provides a strong rationale for its combination with ICIs or other immunotherapies to synergistically and fully mobilize the adaptive and innate immunity against tumor cells. Ongoing prospective studies will evaluate the clinical effect of these combination regimens and their immune effect in CRC and SCCHN and in other indications.

Keywords: ADCC; CTLA-4; Cetuximab; Immunotherapy; PD-1; PD-L1.

Fig. 1.

Rationale for combination therapy. Complementary and synergistic activities of cetuximab and ICI-based therapies. This Venn diagram describes the known advantages (in black) and challenges (in red) associated with the use of cetuximab and ICIs. The two therapies have complementary properties (eg, when considering TTR and mobilization of Treg), and thus, the combination of cetuximab and ICIs may yield high levels of immunostimulation and a durable response in a high percentage of patients. ADCC, antibody-dependent cell-mediated cytotoxicity; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; NK, natural killer; ORR, overall response rate; PD-L1, programmed death-ligand 1; RR, response rate; Treg, regulatory T cells; TTR, time to response. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2A.

Mechanism of cetuximab-mediated immune activity. The binding of cetuximab to EGFR and to the CD16 receptor on NK and dendritic cells sets off multiple immune actions that can lead to tumor cell targeting and death, including ADCC (innate immunity) and T cell priming (adaptive immunity). CD, cluster of differentiation; CXCL, chemokine (C-X-C motif) ligand; CXCR, C-X-C chemokine receptor; EGFR, epidermal growth factor receptor; F, phenylalanine; IgG1, immunoglobulin G1; IFNγ, interferon-γ; IL, interleukin; NK, natural killer; V, valine.

Fig. 2B.

Immunosuppressive mechanisms that can account for the dampening of cetuximab-mediated immune activity. Immunostimulatory activity initiated by the binding of cetuximab to EGFR and to the CD16 receptor on NK and dendritic cells sets off feedback immunosuppressive mechanisms, including Treg tumor infiltration and expression of immune checkpoints on tumor and immune cells. CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCL, chemokine (C-X-C motif) ligand; CXCR, C-X-C chemokine receptor; EGFR, epidermal growth factor receptor; HLA, human leukocyte antigen; IFNγ, interferon-γ; IL, interleukin; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-1, programmed death receptor 1; PD-L1, programmed death-ligand 1; TGFβ, transforming growth factor β; Treg, regulatory T cells.

Fig. 2C.

Mechanisms of synergy between cetuximab and ICIs (or other immunotherapies). ICIs may synergize with cetuximab-driven immune activity by disinhibiting immune effector cells present in the intratumoral space. CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCR, C-X-C chemokine receptor; EGFR, epidermal growth factor receptor; IFNγ, interferon-γ; IL, interleukin; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-1, programmed death receptor 1; PD-L1, programmed death-ligand 1; TGFβ, transforming growth factor β; Treg, regulatory T cells.