The Right Partner in Crime: Unlocking the Potential of the Anti-EGFR Antibody Cetuximab via Combination With Natural Killer Cell Chartering Immunotherapeutic Strategies

Abstract

Cetuximab has an established role in the treatment of patients with recurrent/metastatic colorectal cancer and head and neck squamous cell cancer (HNSCC). However, the long-term effectiveness of cetuximab has been limited by the development of acquired resistance, leading to tumor relapse. By contrast, immunotherapies can elicit long-term tumor regression, but the overall response rates are much more limited. In addition to epidermal growth factor (EGFR) inhibition, cetuximab can activate natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC). In view of the above, there is an unmet need for the majority of patients that are treated with both monotherapy cetuximab and immunotherapy. Accumulated evidence from (pre-)clinical studies suggests that targeted therapies can have synergistic antitumor effects through combination with immunotherapy. However, further optimizations, aimed towards illuminating the multifaceted interplay, are required to avoid toxicity and to achieve better therapeutic effectiveness. The current review summarizes existing (pre-)clinical evidence to provide a rationale supporting the use of combined cetuximab and immunotherapy approaches in patients with different types of cancer.

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

“…Immunotherapeutics, such as immune checkpoint inhibitors, are considered to stimulate immune-mediated anticancer reactivity by interrupting the immune inhibitory pathway. Immunotherapies may result in long-term tumor regression, but the overall response rates are limited, especially for solid tumors ( Baysal et al, 2021 ). HNSCC is an immunosuppressive disease, and immune checkpoint inhibitors are emerging as a promising therapy for patients with HNSCC.…”

Metformin Downregulates the Expression of Epidermal Growth Factor Receptor Independent of Lowering Blood Glucose in Oral Squamous Cell Carcinoma

“…In OSCC tissues, the relationship between EGFR overexpression and poor survival of patients has been repeatedly reported (19,20). The expression of EGFR mediates systemic complications of T2DM that affect the heart, kidneys, and eyes (21).…”

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

“…More sophisticated approaches have been taken to improve efficacy of mAb therapy including the conjugation of mAbs to toxins or therapeutic agents, as well as the generation of bispecific mAbs which recognize distinct epitopes on each end of the molecule. In addition to blocking downstream signaling, IgG mAbs can induce antibody-dependent cell-mediated cytotoxicity (ADCC) via binding of the Fc receptor to immune cells [ 104 ]. Advantages of mAbs include their specificity, effectiveness across many cancer types, ease of conjugation, and low cost compared to other ITs.…”

“…The overall survival of patients receiving cetuximab (10 months) and panitumumab (10.4 months) was similar in the phase III ASPECCT study, indicating their comparable efficacy (HR 0.97; 95% CI 0.84–1.11) [ 2 , 105 ]. Anti-EGFR mAbs are thought to induce ADCC via binding of the Fc receptor to immune cells, though the extent of ADCC induction across EGFR inhibitors varies and the contribution of ADCC to the mechanism of cetuximab and panitumumab is questionable [ 2 , 104 ]. New anti-EGFR mAbs in development such as GA201 and imgatuzumab have been glycoengineered to enhance intrinsic ADCC induction [ 106 , 107 ].…”