Novel treatments using PD1 inhibitors for advanced and metastatic cutaneous squamous cell carcinoma

KEYWORDS:

• Cutaneous squamous cell carcinoma
• programmed cell death protein
• PD1
• cancer
• immunotherapy
• tumor mutation burden

1. Introduction

Cutaneous squamous cell carcinoma (SCC) accounts for the second most commonly occurring nonmelanoma skin cancer whereas basal cell carcinoma (BCC) is the first. Metastatic and locally advanced cutaneous SCC have poor response to surgery or radiotherapy; however, systemic therapies can be an alternative option for patients that are not candidates for local therapies.

The most common therapeutic regimens are chemotherapy and epidermal growth factor receptor (EGFR) inhibitors [1–3]. However, some studies have reported the low efficacy of cytotoxic chemotherapies (cisplatin, 5-fluorouracil (5-FU), bleomycin, and doxorubicin) and EGFR inhibitors [4,5]. Due to the fact that cutaneous SCC in the advanced stage has limited response to common therapies, investigations into systematic therapies with better response rates are crucial [6,7].

Retrospective studies indicate that tumor mutational burden (TMB) is a predictive biomarker associated with response of the disease to immunotherapy. Previous studies have shown that tumors with high mutational burden express more neoantigens which help the immune system to target tumors [8–10]. The latest programmed cell death protein 1 (PD1) inhibitor, cemiplimab (Libtayo, REGN2810), was approved by the Food and Drug Administration (FDA) in 2018 for the treatment of advanced cutaneous SCC which is not responsive to surgery and common therapies [5,11].

The combination of PD1 inhibitors with other therapies such as radiation may increase the response in advanced cutaneous SCC [12]. Administration of PD1 inhibitors have shown higher response rates in tumors with high TMB compared to those with lower TMB; however, other variables must be considered [13,14]. Therefore, other predictive biomarkers need to be investigated to increase the objective responsive rate in patients. In this article, we aimed to review the studies on the application of PD1 inhibitors in advanced cutaneous SCC and their combinatory therapies as a strategy to increase treatment efficacy.

2. Cutaneous SCC

Although SCC is less common than BCC, the ratio of SCC to BCC has been estimated 1:1 in 2012 in the United States. It is reported that the incidence of skin cancer increased about 100% from 1996 to 2012 [15].

There are different therapies available depending on the stage of disease. Most of the cutaneous SCCs can be removed by surgical excision except a small proportion (almost 2–4%) which have different aspects like tumor location, metastasis to lymph nodes or distant organs, etc. High mortality rates are reported in patients with cutaneous SCC whose tumors have features such as metastasis to lymph nodes, tumor diameter greater than or equal to 2 cm, and extracapsular spread [16]. Considering alternative treatments for these patients, the most common regimens are chemotherapy and EGFR inhibitors [2]. The objective response rate of 28% is reported for Cetuximab, an EGFR inhibitor [1], and objective response rates in a range of 10–31% are reported for the administration of other drugs associated with inhibition of EGFR such as dacomitinib, erlotinib, and panitumumab [1,17]. Moreover, a mean overall survival of 8.1 months in a phase 2 study of cetuximab in patients with advanced cutaneous SCC was reported [4]. This low response rate and short mean overall survival time show the low efficacy of common therapies.

3. PD1 inhibitors

PD1 inhibitors are recently approved by the FDA for the treatment of cutaneous SCC with higher efficacy. PD1 and PD1 ligands (PDL1) participate in the regulation of immune responses. The binding of PD1 expressed on T and B lymphocytes and PDL1 on peripheral tissues attenuates T cell responses and further tissue damages [18]. The effect of PD1 on T cell is mediated by the regulation of CD28 in order to maintain peripheral tolerance [19]. Chronic antigen stimulation causes clones of T cells that are active but less potent because of PD1and PDL1 which are attenuating the immune system, this phenomenon is called T cell exhaustion [20]. This also happens in the tumor microenvironment which leads to lower immune response against tumor [21]. It is reported that PD1 blockade prevents this signaling regulation and increases the cytotoxic capacity of the immune system in spite of PDL1 expression [22].

A phase II single-arm trial of cemiplimab enrolled 78 patients with advanced cutaneous SCC who did not receive other therapies. The objective response was observed in 34 of 78 patients (44%; 95 CI). Moreover, there were 10 patients (13%) with a complete response and 24 (31%) with partial response. The most common adverse effect was hypertension in six patients (8%) and pneumonia in four individuals (5%). The responses were rapid and consistent responses were predictable with longer follow-up periods. These higher response rates demonstrated that cemiplimab can be considered a promising therapy for patients with poor prognosis and lack of an effective treatment [5].

4. Increased efficiency with combinative therapies

4.1. PD1 inhibitors and IL7 cytokine

Some types of tumors can induce some suppressive changes in CD8 + T cells losing anti-tumor functions like loss of CD27 and CD28 [23,24]. These PD1+ CD8 + T cells suppress the proliferative capacity of normal autologous T cells. PD1 inhibitors slow the tumor growth through retrieving normal cytotoxic CD8 + T cell functions [23]. There are studies that showed antitumor immunity capacity can also be increased by IL7 treatment which protect T cells from phenotypic alterations and loss of CD27 and CD28 [24]. The PD1 inhibitor and IL7 cytokine combinative therapy in vivo is reported to synergize the antitumor effects of PD1 inhibitors [23].

4.2. PD1 inhibitors and radiotherapy

The combination of PD1 inhibitor therapy and radiotherapy can have optimal effects and increase response [25]. Low dose fractioned radiotherapy leads to polyclonal T cell infiltration and expansion in the tumor environment. Radiotherapy increases the expression of PDL1 in the tumor microenvironment restricted to the radiated area. This is one of the reasons that the combination of PD1 inhibitors and radiotherapy has a synergetic effect on tumor regression [26]. A case report of a 65-year-old white man with cutaneous SCC of scalp lesion (4.0 cm *3.5 cm) showed tumor regression through initial radiotherapy for 3 months and subsequent treatment with pembrolizumab, a PD1 inhibitor, for 12 months. During the follow-up period (19 months), the patient had no evidence of the disease [12]. In palliative radiotherapy, the regression of metastatic tumors distant to the irradiated tumor site is a rare event called ‘abscopal effect’ [27]. This was first reported on a female patient with melanoma undergoing treatment with radiotherapy and ipilimumab [28]. This is caused by cellular and molecular feedback mechanisms triggered by synergetic effect of radiotherapy on tumor regression, as described above [29]. The combination of various immunotherapies and radiotherapy is complex and requires further studies on various aspects such as the optimal radiotherapy timing, the location and size of the tumors, and lowering side effects. [30].

5. Predictive biomarkers

All patients with cutaneous SCC can benefit from a higher chance of response in immunotherapies compared to standard chemotherapies. However, predictive biomarkers are needed to be investigated in order to increase the efficiency of treatments by selection of patients who will benefit more from PD1 inhibitor therapies. Currently, there is no promising validated predictive biomarker but many candidates are being investigated including PD-L1 expression, HPV+ tumors, TMB, and the microbiota [31].There is limited data available about predictive biomarkers and divergent results of studies could not reach firm conclusions. For example, there are reports of high response rates to PD1 inhibitors in tumors with higher PD-L1 expressions [32]; however, tumors with lower expression of PD-L1 have also been reported to respond to PD1 inhibitors [33]. This may be due to different methods of PD-L1 expression measurement and an unclear threshold of PD-L1 expression considered positive [34]. Moreover, controversial results were reported that HPV+ tumors would respond to PD1 inhibitors more than HPV- tumors. Although some studies have shown positive effects of HPV infection on tumor response, some others have indicated higher response rates in HPV- tumors than HPV+ tumors with high TMB [35,36]. These higher response rates may be attributed to other effective factors such as a high load of neoantigens and PD-L1 expressions which is not known completely yet [36,37].

6. Tumor mutational burden

Studies supported the fact that tumors with higher TMB have an increased response rate and this significant correlation shows the possibility of TMB as a predictive biomarker [14]. Approaches on standardizing TMB measurement give the chance to validate TMB as a predictive biomarker [31].

7. Microbiota

The only biomarker that may have the potential to predict patient response is an individuals’ microbiota. The microbiota of the gastrointestinal tract is associated with immune dysregulation, tumor initiation, and progression. The mechanism of their association is not yet known but studies indicated that the microbiota have effects on antitumor immune system response and anticancer therapies including immunotherapies. The correlation of microbiota and prediction of response to immune checkpoint inhibitors (ICI) is not yet known [31]. A study reported negative correlation of oral microbiota in contrast to positive correlation of intestinal microbiota and treatment outcomes in melanoma patients [38]. Further research is currently in progress to understand the relationship of oral and intestinal microbiota with treatment response in cutaneous SCC [31].

8. Immunotherapy in immunodeficiencies

Primary or secondary immunodeficiencies are developmental problems in the immune system which can lead to a higher risk of malignancy formations. Immunosuppressive medications following organ transplantation may increase the susceptibility of cancer development, most commonly cutaneous SCC [39]. As the immune system does not react properly to cancerous cells and antigens in immunocompromised patients, the idea of using immunotherapy helps improve the functions of immune system [40]. However, immune-related adverse events are important side effects of immunotherapies [41]. Because of the higher risk of immune dysregulation in immunosuppressed patients, there are only a few studies on ICI administration [42]. These studies have reported various outcomes including minor side effects, neuromuscular weakness syndromes, etc. [43,44]. Overall, as advanced or metastatic cutaneous SCC develop to a significant part in immune-suppressed patients, further studies considering this population are necessary to introduce effective immunotherapies.

9. Conclusion

The reason why not all patients respond to PD1 inhibitors is not well known but various aspects must be considered to increase the efficiency of this therapy. Standardized TMB measurement is one of the ways to select patients with improved response rates. Predictive biomarkers will help to choose patients with a higher chance of response to treatment. Oral and intestinal microbiota are one of the choices but need further study to understand the exact relationship. Various combination therapies such as radiotherapy and cytokine therapy can be applied to see an enhancement in the efficiency of PD1 inhibitors. Reports on using other PD1 inhibitors alone or in combination with other therapies for refractory settings are summarized in Table 1.

Table 1. Reports on other PD1 inhibitor usage alone/in combination with other therapies for refractory settings

Report	Intervention
Cutaneous Basaloid Squamous Cell Carcinomas [45]	Combined Systemic and Intratumoral Administration of Human Papillomavirus Vaccine
Advanced cutaneous squamous cell carcinoma resistant to chemotherapy [46]	Cetuximab
Advanced non-resectable cutaneous squamous cell carcinoma [47]	Pembrolizumab and concurrent hypo-fractionated radiotherapy
Advanced rare cancers including cSCC [48]	Pembrolizumab

10. Expert Opinion

Due to the high mortality of advanced and metastatic cutaneous squamous cell carcinoma, treatments with higher responsive rates are needed as we know the current therapies are not highly efficient to decrease the mortality rates. Check point inhibitors are novel treatments which have increased the responsive rates in recent studies. The combination therapies with PD1 inhibitors have shown promising results in cutaneous SCC patients which necessitates further investigation on its biological mechanisms to improve the effects of the treatment. This must be one of the future goals for the treatment of this disease which is seemingly very hopeful. It is important to consider the exact mechanism underlying this therapy in order to predict the treatment response by finding more accurate predictive biomarker. Therefore, it is possible to choose patients with a higher possibility of treatment response and decrease the side effects of this immunotherapy on patients which have poor responses. In research perspective, we shouldn’t miss immunosuppressed patients who are more vulnerable to cancers with an abnormal immune system. This novel treatment will improve our therapeutic options for patients with advanced cSCC.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.