Monoclonal antibodies for the treatment of squamous cell carcinoma: A literature review

Abstract Background Squamous cell carcinoma (SCC) is a relatively common and heterogenous malignancy of different organs, such as the skin, esophagus, and lungs. Although most cases experience good survival with surgical methods, management of advanced types of the disease remains challenging. Several modalities, including different chemotherapy regimens and immunotherapies, have been investigated in this matter, among which Monoclonal antibodies (Mabs) are one of the most promising ones. Since the development of Mabs, they have been widely used to treat different diseases. Mabs have shown significant efficacy with high specificity along with acceptable safety, which makes them a favorable option in cancer therapy. In this article, we aimed to review the different aspects of using Mabs in SCC therapy. Recent Findings We found that treating with different Mabs has shown excellent efficacy accompanied by acceptable safety in treating SCC of different organs. Therefore, Mabs are considered great options in the treatment of SCC, especially in advanced cases. Overall, two highly potent types of Mabs in SCC therapy are anti‐EGFR Mabs and checkpoint inhibitors, especially Cetuximab, Nimotuzumab, and PD‐1 inhibitors. Bevacizumab is also a promising option as adjuvant therapy to other modalities. Conclusion Although some Mabs have shown promising outcomes in SCC therapy, their application as a part of cancer treatment depends on further investigations regarding cost‐effectiveness and predictors of response. FDA has approved several Mabs in SCC therapies, and Mabs may have a crucial role in this era in the near future, especially in treating head and neck and esophageal SCC and metastatic lung cancer.


| INTRODUCTION
Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer and a common malignancy in many countries. 1,2 In the United States, around 3.5 million none-melanoma skin carcinomas are diagnosed yearly, 700,000 of which are new cases of SCC, resulting in 2500 deaths per year. 3 The most common risk factor for SCC is lifetime ultraviolet (UV)-induced nuclear damage. 4 SCC involving the head and neck area may be particularly aggressive. Oral SCC accounts for 90% of all oral malignancies. 5 For several years, the most common treatments for SCC included surgery, chemotherapy, radiation, and interferon-based therapies. 6,7 Rejection of common therapies in some cases of cutaneous squamous cell carcinoma (CSCC) with local contention or distant metastasis caused great doubt in traditional methods. 8 On the other hand, many studies confirmed several serious adverse effects of surgery and chemotherapy in treating skin cancers. 7 Therefore, discovering new weaknesses and side effects of traditional treatments has led researchers to achieve more efficient and safer anti-cancer therapies. 9,10 Understanding the network of receptors and ligands in different cancers and their mechanism has provided promising agents to target. 11 Studies on head and neck squamous cell carcinoma (HNSCC) demonstrated that overexpression of epidermal growth factor receptor (EGFR) increases radio-resistance. 12 On the other hand, proliferation and metastasis of SCC are relatively associated with specific inflammatory cytokines such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), hepatocyte growth factor (HGF), and IL-6. 13,14 Targeting these factors to restrict SCC has become popular in recent research.
The main treatment options for SCC encompass curettage and electrodesiccation, laser therapy, freezing, photodynamic therapy, simple excision, Mohs surgery, radiation therapy, chemotherapy, targeted drug therapy, and immunotherapy based on monoclonal antibodies ( Figure 1).
Immunotherapy based on Mabs is considered a reliable treatment for several disorders and has become a novel component of main anti-cancer therapies in recent years. 15 Further studies on Mabs, such as cemiplimab, cetuximab, bevacizumab, and atezolizumab, developed different therapies to target specific ligands or receptors and prevent tumor activities. 16 These successful findings have continued to date, and many trials have demonstrated promising anti-cancer effects of these Mabs, such as bevacizumab and durvalumab together with or without traditional treatments. [17][18][19] Here, we review the anti-cancer properties and potential side effects of Mabs and compare their efficiency and safety.
F I G U R E 1 A summary of the current treatment options for SCC: main therapy for SCC includes curettage and electrodesiccation, laser therapy, cryosurgery, photodynamic therapy, simple excision, Mohs surgery, radiation therapy, chemotherapy, targeted drug therapy, and immunotherapy based on monoclonal antibodies.

| METHOD
We searched electronic databases of PubMed, Scopus, Web of Science, and Google scholar. We extracted articles related to Mab and SCC treatment up to June 2022. Medical Subject Headings (MeSH) terms were included. We obtained the full texts of relevant articles, and the relevant articles in the reference lists were also searched manually ( Figure 2). The duplicates were removed using End note X9. Articles with irrelevant titles and studies other than clinical trials were removed. In the following, we will describe the mechanisms of Mabs in treating SCC (Table 1).

| MONOCLONAL ANTIBODIES
The immune system's ability to recognize foreign cells enables the body to defend against cancerous cells. 20 Hybridoma technology, the invention of Milstein and Kohler, brought the availability of Mabs. 21 Immune-based therapies, Mabs, predominantly aim to strengthen immune responses against tumor cells. Different strategies have been suggested in the last decades to stimulate T cells in favor of targeting tumor cells, such as enhancing innate immune activity and inhibiting suppressive pathways. 22,23 The mechanism by which Mabs treat cancer cases is by presenting tumor cells to destructive processes of the immune system. 16 Mabs can activate complement-dependent cytotoxicity (CDC) via binding to complement C1q to start the formation of the complement cascade, which can eventually destroy aimed cells.
Mabs can also induce antibody-dependent cellular cytotoxicity (ADCC), which results in the eradication of the target cell as well. 24 In general, agglutination, inactivation of signaling proteins, or occupation of receptors are the fundamental mechanisms the antibodies employ to protect the body against cancer. 25 Enhancing knowledge about the mentioned mechanisms has provided several potential occasions to target tumor pathogenesis. The growth factor receptors activate along with the tumor progression.
Mabs may decrease tumor activities by inactivating the binding of the ligands to these receptors or by blocking signaling. This mechanism can ultimately lead to cell death induction or increased sensitivity of tumor cells to therapeutic drugs. 26 In another condition, bevacizumab blocks vascular endothelial growth factors (VEGFs) receptors and inhibits tumor-mediated angiogenesis. 27 Furthermore, numerous F I G U R E 2 PRISMA 2022 flow diagram studies suggest that Mabs play a potential role in triggering the acquired immunity against malignancies. 28 Consequently, Mabs provided unbelievable oncological purposes in several approaches. 29 In addition, many studies approved their therapeutic applications in other disorders, such as inflammation, infection, and cardiovascular disease. 30 Therefore, many recent trials introduced Mabs as an effective therapeutic approach in cancer treatments. 31 Using Mabs alone or in combination with other methods showed encouraging outcomes in controlling SCC. 32 Cetuximab, for instance, has been used in both directions to treat head and neck squamous cell carcinoma (HNSCC) and proven its efficacy. 33,34 The average halflives of Mabs last for 18-21 days. A reduction in half-lives might occur due to adverse binding to unspecific targets. 35 Ectodomain shedding of Mabs receptors is another issue which seems to hinder reaching the target cells. 36 Antidrug antibodies (ADAs) generation can also be a result of provoking the patient's immune system. 37 However, chemotherapy seems to leave harsher side effects. 38 Altogether, Mabs are known to function through various mechanisms in treating SCC. Some Mabs target EGFR, HER2, IGF-1R, HGF, and VEGF; others may be checkpoint inhibitors (including Mabs to PD-1, CTLA4, and NKG2A) or tumor-targeting Mabs such as U36 and Mab E48. In the following pages, we reviewed the Mabs in SCC immunotherapy. Besides, clinical trials proved that cetuximab inhibits invasion, angiogenesis, and metastasis. 42 The overactivation and high expression of EGFR in almost all HNSCC cases (over 90%) have been reported. 43,44 Consequently, elevated EGFR promotes oncogenesis and plays an independent poor prognostic role in HNSCC. 44,45 Furthermore, EGFR blockage makes tumor cells susceptible to radiation; on the other hand, radiotherapy promotes the expression of EGFR. [45][46][47] Therefore, EGFR-blocking would be a good choice to improve the outcome of patients in comparison to radiotherapy alone. Previous studies showed that combining cetuximab and radiotherapy restricts HNSCC more efficiently and decreases mortality and adverse effects. 45 Controversial findings on cetuximab efficiency and toxicity have been reported. 48,49 Recently, in a novel study, Fushimi et al. demonstrated that even though the combination of cetuximab and paclitaxel increased median progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/MHNSCC), this regime led to some adverse effects, such as rash-acneiform, anemia, and neutropenia. 50

56
Unresected, locally AHNSCC Local-regional control at 2 years was 51% in the radiotherapy plus panitumumab group and 61% in the chemoradiotherapy group 58 Unresected, locally AHNSCC Local-regional control at 2 years was 61% in G2 and 68% in G1. No significant differences in the results

| Ficlatuzumab
Ficlatuzumab is a potent humanized IgG1 Mab that binds the hepato- HNSCC progression. 83 Another study showed that ficlatuzumab, in combination with cetuximab has an appropriate safety profile and demonstrates promising cytotoxic effects in a refractory population of HNSCC patients. 84,85 In conclusion, targeting C-Met by ficlatuzumab seems a potentially promising method to manage SCC, according to recent studies.

| Anti-vascular endothelial growth factor (anti-VEGF)
VEGF expression has been correlated to tumor invasion, venous and lymphatic invasion, lymph node metastasis, and tumor stage in ESCC.
Therefore, it may be involved in the progression of esophageal carcinoma via its angiogenesis and lymphangiogenesis effects. 86

| Bevacizumab
Bevacizumab, a humanized IgG1 Mab, functions as an anti-VEGF recombinant Mab with the affinity to bind all VEGF-A isoforms. 17 The primary mechanism of bevacizumab activity includes binding to VEGF-A and preventing it from joining VEGFR1 and VEGFR2. 17,19 Bevacizumab has proven beneficial therapeutic properties in the treatment of different cancers, including recurrent cervical, 87 colorectal, 88 renal-cell, 89 breast. 90 VEGF expression correlates to tumor invasion, venous and lymphatic invasion, lymph node metastasis, and tumor stage in ESCC. Therefore, it may be involved in the progression of esophageal carcinoma via its angiogenesis and lymphangiogenesis effects. 86 Adding a particular regimen of bevacizumab to chemotherapy and radiation results in a 95% positive response with relatively equal toxicity to other modalities, which confirmed the efficacy of adding bevacizumab and erlotinib to standard first-line treatment. 91 Besides, A middle-eastern study proved bevacizumab as a promising treatment for HNSCC due to its negative effects on VEGF secretion. 92 In addition, a combination of bevacizumab with cisplatin and radiation therapy improved the 2-year OS and PFS with a few adverse events, such as a significant increase in myelosuppression and leukopenia. 93 In a phase II study, adding bevacizumab to pemetrexed in patients with HNSCC enhanced median OS to 11.3 months and treatment rate to 30%; however, toxic outcomes of bevacizumab application included significant bleeding in 15%, neutropenia in 10%, and infection in 12.5% of the patients and one death due to sepsis. 94 98 On the other hand, a randomized phase II study showed that Duligotuzumab has low efficiency in the R/MHNSCC treatment outcomes. 99 Putting an endpoint to controversies, recent studies on this dual antibody demonstrated that Duligotuzumab has positive effects on ionizing radiation. 100

| DT-IgG
For higher efficiency in cancer therapy, scientists aimed to design antibodies that can simultaneously affect more than one receptor. 101 One of these antibodies is DT-IgG, a fully humanized dual target antibody to EGFR and VEGF that restricts key growth factors. 102 (Table 3). 106 118 In addition, a study on a patient with CSCC showed that complete remission was achieved within 6 months of immunotherapy with cetuximab and nivolumab. 119 In the case of cost-effectiveness, studies have argued that although nivolumab increases OS, it is not a cost-effective option for treating R/MHNSCC. 120,121 In a study conducted by Yamakawa  In an attempt to profile the biomarker aspects of pembrolizumab In a recent phase II study, the combined therapy of pembrolizumab with afatinib was tested. Additionally, a biomarker quantification was also performed. Twenty-nine patients with recurrent or metastatic HNSCC whose disease was refractory post platinum therapy were included. The conclusion suggested that afatinib may enhance pembrolizumab efficacy with improved ORR. Also, antigen presentation and cytotoxicity induced by natural killer cells (NK cells), indicated upregulation in the tumor tissue. Nonetheless, treatment toxicity of grade ≥3 was reported in 37.9% of the cases, which can be an issue of concern in applying this combination. 138 A study performed by Tao

| Durvalumab
Durvalumab is a human IgG1 kappa Mab blocking PD-L1 on malignant cells from binding to PD-1 and CD80 on T cells, subsequently allowing higher T cell activation and anti-cancer activity. 140 Taken together, due to the high survival of patients using durvalumab, it is a novel promising treatment for HNSCC not only in patients with high PD-L1 profiles but also in patients with low PD-L1 manifestations. 142,144 In patients with esophageal squamous cell carcinoma, Park et al.

| Cemiplimab
Cemiplimab, a high-affinity IgG4 Mab, blocks the PD-1/PD-L1 pathway. 150 The treatment of CSCC with cemiplimab is more efficacious compared to platinum-based chemotherapy in terms of OS. 151  Altogether, more studies are required to find new methods and to consider the side effects of ipilimumab, to prove safer approaches.

| Tremelimumab
Tremelimumab is a fully human IgG2 Mab that targets cytotoxic Tlymphocyte-associated antigen-4 (CTLA-4) and exhibits antitumoral effects by blocking the CTLA-4 pathway. 164 Phase II research investigated the efficiency of tremelimumab as monotherapy. There were about 244 patients in each group. One group received durvalumab as monotherapy (group 1), the second group received both tremelimumab and durvalumab as combined therapy, and the third group was standard of care (SoC). The results showed no marked differences in OS between durvalumab monotherapy or combined use of durvalumab and tremelimumab versus SoC.
However, survival rates increased in 12-24 months, and response rates showed that durvalumab was a beneficial therapeutic agent. 18 Ferris

| Monalizumab
Monalizumab is the first-in-class humanized IgG4 Mab targeting NKG2A, which enhances NK cell activity against various tumor cells and rescues CD8+ T cell function. It also stimulates NK cell activity against antibody-coated target cells. 168 The combination of monalizumab and cetuximab reduced almost all cetuximab-mediated side effects and showed more reliable outcomes. 169 7 | TUMOR TARGETING: MAB U36 AND MAB E48 Using cMab U36 labeled with 211Astatine showed reliable results in treating rats with HNSCC; on the other hand, combining this radioimmunotherapy with cetuximab revealed better results in controlling carcinoma and drew attention to interactions between CD44v6 and epidermal growth factor receptor (EGFR). 170 Other possible underlying mechanisms of action are yet to be discovered (Figure 3 summarizes all the monoclonal antibodies used for treating SCC).

| Lung squamous cell carcinoma
Several Mabs, including nimotuzumab, bevacizumab, ipilimumab, necitumumab, and pembrolizumab have shown acceptable efficacy in treating Lung SCC as a type of non-small cell lung cancer. 65,68,161,[188][189][190][191][192] FDA has approved the combination of nivolumab and ipilimumab as the first-line treatment of metastatic non-small cell lung cancers that express PD-L1 with no genomic tumor aberrations in EGFR or anaplastic lymphoma kinase (ALK). 193 Pembrolizumab has also been approved by FDA in combination with carboplatin and either paclitaxel or nab-paclitaxel as the first-line treatment of metastatic squamous non-small cell lung cancer. 194 Mabs are the potential widely used future treatment of metastatic lung SCC.