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Khorasanchi, A.;  Wu, R.;  Kendra, K.;  Verschraegen, C. Immunotherapy Drugs and Combinations of HNCSCC. Encyclopedia. Available online: https://encyclopedia.pub/entry/40486 (accessed on 31 March 2026).
Khorasanchi A,  Wu R,  Kendra K,  Verschraegen C. Immunotherapy Drugs and Combinations of HNCSCC. Encyclopedia. Available at: https://encyclopedia.pub/entry/40486. Accessed March 31, 2026.
Khorasanchi, Adam, Richard Wu, Kari Kendra, Claire Verschraegen. "Immunotherapy Drugs and Combinations of HNCSCC" Encyclopedia, https://encyclopedia.pub/entry/40486 (accessed March 31, 2026).
Khorasanchi, A.,  Wu, R.,  Kendra, K., & Verschraegen, C. (2023, January 23). Immunotherapy Drugs and Combinations of HNCSCC. In Encyclopedia. https://encyclopedia.pub/entry/40486
Khorasanchi, Adam, et al. "Immunotherapy Drugs and Combinations of HNCSCC." Encyclopedia. Web. 23 January, 2023.
Immunotherapy Drugs and Combinations of HNCSCC
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This entry is adapted from the peer-reviewed paper 10.3390/cancers14215325

Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer. A majority of patients present with localized disease, but some can present with locally advanced or metastatic disease. Most of these advanced cases occur in the anatomical head and neck region and are associated with more aggressive disease, necessitating prompt and effective treatment. Prior to the emergence of immunotherapy, systemic treatment options were limited to platinum-based chemotherapy and salvaged with targeted epidermal growth factor therapy. These therapies were associated with poor efficacy and increased toxicity in an often frail, older population. Immunotherapy has dramatically improved outcomes in this patient population due to its favorable side effect profile, durable treatment response, and improved overall outcomes. 

cutaneous squamous cell carcinoma head and neck immunotherapy immune checkpoint inhibitors

1. Introduction

Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer, and most cases develop in the head and neck anatomical area (HNCSCC) [1][2]. The main risk factors of HNCSCC are chronic exposure to ultraviolet (UV) radiation, age, lighter skin complexion, and immunosuppression [3]. It is a disease of older age, more prominent in men than women, with an incidence of 450 cases per 100,000 person years in the US and a lifetime risk of about 10% [4]. Multiple primary cancers usually develop over time. In more than 90% of cases, HNCSCC is a localized disease, which can be successfully treated with curative surgery or radiotherapy (RT) [5], as described in the National Comprehensive Cancer Network (NCCN) guidelines [6][7]. Less than 5% of cases are classified as locally advanced unresectable or metastatic disease (mHNCSCC), for which systemic treatment is necessary [6]. Furthermore, CSCC within the head and neck region compared to other disease sites is associated with poorer outcomes. Specifically, tumors involving the ear, temples, and lips are associated with a higher risk of recurrent and metastatic disease [7]. Therefore, aggressive treatment of HNCSCC is necessary to achieve optimal outcomes. Other characteristics associated with a poor prognosis include large tumors (>2 cm diameter) with significant depth of invasion (>6 mm), perineural involvement, and poorly defined, undifferentiated tumors [7][8].
Until the advent of immunotherapy, systemic therapies for HNCSCC were limited to cytotoxic platinum-based chemotherapy and salvaged with targeted therapy inhibiting the epidermal growth factor receptor (EGFR) [9]. These therapies are associated with poor response rates, short duration of response, and substantial morbidity and toxicity, especially in patients of advanced age [10][11][12][13]. Since the Food and Drug Administration (FDA) approval of cemiplimab in 2018 and pembrolizumab in 2020, immunotherapy has become the standard of care for patients with locally advanced or mHNCSCC that is not amenable to curative surgery or RT [14]. These drugs have demonstrated overall response rates (ORRs) of approximately 40–50%, with higher ORRs seen in tumors with a higher mutational burden (TMB), due to increased neoantigen expression [14][15][16]. Interestingly, high TMB has been shown to predict response to immune checkpoint blockade in cancers (including lung, melanoma, and bladder) where there was a positive correlation between CD8 T cells and neoantigen load [17].
Immune checkpoint proteins serve as key regulators of the immune system’s response to cancer cells. T-cell activation requires a two-step process: (1) recognition of peptides via the T-cell receptor, and (2) interaction of coregulatory proteins (immune checkpoints) expressed on T cells, with partner proteins on tumor cells. Activation of these immune checkpoints may exhibit either stimulatory or inhibitory immune effects. Under normal circumstances, immune checkpoints ensure an appropriate immune response, while avoiding destruction of healthy tissue and immune hyperactivation as seen in autoimmune diseases. Programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are examples of immune checkpoints that have been studied extensively in cancer treatment. Upon activation, PD-1 and CTLA-4 deliver inhibitory signals to T cells resulting in T-cell inactivation. Immune checkpoint inhibitors (ICIs) block these proteins, resulting in an augmented anti-tumor immune response [18][19].

2. Nivolumab

While not officially approved for use in patients with non-melanoma skin cancer, other ICIs may be effective in treating patients with advanced CSCC. Their efficacy thus far has been limited to published case reports and case series.
Nivolumab, a monoclonal antibody targeting PD-1, was assessed in 3 patients with recurrent CSCC who had previously been treated with chemotherapy. A PR was noted in 2 patients, and 1 patient experienced stable disease following 3 months of treatment [20]. Chen et al. described a patient with poorly differentiated advanced CSCC who achieved CR following treatment with nivolumab and cetuximab [21]. Presently, there are several ongoing clinical trials (NCT03834233, NCT04204837) evaluating the efficacy of nivolumab in the treatment of locally advanced and metastatic CSCC [22].

3. Ipilimumab

Ipilimumab is a CTLA-4 inhibitor approved for use in metastatic melanoma patients. Similar to nivolumab, its efficacy has been limited to published case reports. Day et al. described a patient with metastatic CSCC, previously treated with chemotherapy, who achieved a CR following 4 cycles of ipilimumab [23].

4. Immunotherapy and Radiation Therapy

Another innovative strategy is the combination of immunotherapy with RT. Radiation-induced damage to cells has several effects on the immune system, including T-cell priming and upregulation of immune checkpoint molecules on tumor cells, which in turn can facilitate increased immune-mediated cell death when combined with ICIs [24]. This treatment approach is currently being evaluated in the UNSCARRed study, investigating the effects of RT and avelumab in patients with unresectable CSCC (NCT03737721).

5. Immunotherapy and EGFR Inhibitors

The I-TACKLE trial—an open-label, nonrandomized, phase II trial in 43 patients with locally advanced or metastatic CSCC conducted in 3 Italian centers—investigated the addition of an anti-EGFR agent cetuximab to pembrolizumab to counteract pembrolizumab resistance. Forty-four percent of patients experienced a response to pembrolizumab with a cumulative ORR of 63%. Twenty-one patients had primary resistance to pembrolizumab and received the combination therapy [25]. The addition of cetuximab led to a response rate of 38% and is hypothesized to produce a synergistic effect as it contributes to NK cell activation, which in turn activates negative feedback controls via increased expression of PD-1, PD-L1, and CTLA-4 [26].

6. Oncolytic Viruses

Oncolytic viruses (OVs) are injected into tumors and exert both local and systemic antineoplastic effects within the body. Locally, OVs selectively infect and grow within the injected tumor, resulting in tumor lysis and cell death [27]. Tumor lysis leads to the release of antigens and danger signals, which promote enhanced dendritic cell antigen presentation, T-cell priming, and T-cell mediated cytotoxicity within the injected tumor. Additionally, OVs can promote the migration of tumor-specific T cells to uninjected tumor cells and exert distant antineoplastic effects [28]. Finally, increased interferon (IFN) gamma signaling leads to upregulation of PD-1 on host T cells and PD-L1 on tumor cells, resulting in an augmented antineoplastic effect when combined with PD-1 blockade [29].
RP1 is a genetically modified herpes simplex OV. Niu et al. reported promising results in the phase I/II IGNYTE trial, in which patients with HNCSCC and other tumor types achieved a CR rate close to 50% when treated with RP1 monotherapy or in combination with nivolumab. Tumor regression was observed in both injected and non-injected distant lesions following RP1, suggestive of a systemic treatment response [30]. A phase II trial investigating the use of RP1 alone and with cemiplimab in patients with advanced CSCC (NCT04050436) is ongoing. Finally, RP1 is being investigated in a phase IB/II trial of SOTR with CSCC and other advanced cutaneous malignancies (NCT04349436).
Talimogene laherparepvec (T-VEC) is another genetically modified herpes simplex OV currently being studied in CSCC. A recent phase II study interim analysis reported 100% ORR in 7 patients with low-risk CSCC treated with T-VEC [31]. Ongoing clinical trials are investigating combination therapy with T-VEC, including the use of nivolumab (NCT03714828) and panitumumab (NCT04163952).

7. Other Therapies

Two studies are investigating the use of photoimmunotherapy in the treatment of patients with CSCC. This involves the injection of an antibody-dye conjugate, followed by activation with a particular wavelength of light. RM-1995 is composed of an antibody that targets CD25, a receptor with increased expression by regulatory T cells (Treg). This drug conjugate is activated when illuminated by red light, and targets Treg cells within tumors, thus augmenting the antitumor immune response. RM-1995 is given as a single agent as well as in combination with pembrolizumab (NCT05220748). In the other study, ASP-1929 is composed of an EGFR antibody that is also activated by the illumination of red light. ASP-1929 will be given in combination with cemiplimab (NCT04305795).
Another study is exploring the use of an intra-tumoral vaccine injection expressing a DNA plasmid known as IFX-Hu2.0 (NCT04160065). This results in expression of a streptococcal membrane protein within the lesion, which in turn stimulates the immune system and produces a favorable environment for ICI therapy. This phase I study plans to enroll 20 patients with advanced non-melanoma skin cancers (accrual is ongoing).
Additionally, B7-H3 has emerged as a promising molecular target for immunotherapy-based studies. It is an immune checkpoint protein, which exerts inhibitory effects on the immune system via suppression of T-cell activation and proliferation. It is highly expressed in various solid tumors, yet has limited expression in normal tissues. Increased B7-H3 expression has been shown to promote immune escape and tumor growth in head and neck squamous cell carcinoma (HNSCC) stem cells [32]. Furthermore, a 2018 study found B7-H3 to be highly expressed, particularly in immunocompetent patients with CSCC [33]. While there are no current clinical trials involving CSCC patients, B7-H3 has been found to be an effective target in other advanced cancers including HNSCC and melanoma. A recently published phase I/II study found the combination of enoblituzumab, a B7-H3 monoclonal antibody, and pembrolizumab was highly effective (ORR 33%) and well tolerated in patients with advanced solid tumors [34]. Furthermore, interim results from a phase I study of enoblituzumab in combination with ipilimumab in refractory cancers suggested it was well tolerated; however, final study results have not been published yet (NCT02381314).
Finally, several studies are exploring the use of cytokines in combination with immunotherapy, including one phase IB/IIA study evaluating the use of interleukin-7 (IL-7) in combination with atezolizumab in patients with advanced cutaneous malignancies (NCT03901573). IL-7 is critical for the development of naïve and memory T cells, which in turn facilitate an antitumor immune response [6].

References

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Adam Khorasanchi , Richard Wu , Kari Kendra , Claire Verschraegen
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Update Date: 29 Jan 2023
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