SCC originates in squamous cells found in the outer layer of the skin and linings of hollow organs (e.g., mouth, throat, lungs). While localized therapies treat many cases, advanced or recurrent SCC requires systemic intervention. Immunotherapy is a significant advancement that harnesses the body’s own immune system to recognize and eliminate cancer cells throughout the body. This approach differs fundamentally from traditional chemotherapy or radiation.
How Immunotherapy Targets Squamous Cell Carcinoma
Immunotherapy targets immune checkpoints, which normally regulate the immune system’s activity. T-cells, the primary immune cells responsible for killing cancerous cells, possess checkpoint receptors that act as molecular “brakes” to prevent attacking healthy tissues. Cancer cells exploit this system to evade destruction.
Many SCC cells express high levels of Programmed Death-Ligand 1 (PD-L1). When PD-L1 binds to its corresponding receptor, Programmed Death 1 (PD-1), on the T-cell, it sends a powerful inhibitory signal. This interaction engages the T-cell’s “brake,” preventing it from recognizing the tumor as a threat.
Immune checkpoint inhibitors block this inhibitory interaction. These agents are monoclonal antibodies designed to physically attach to either the PD-1 receptor on the T-cell or the PD-L1 protein on the cancer cell. Disrupting the PD-1/PD-L1 pathway effectively releases the “brakes” on the T-cells.
This process re-activates the T-cells, allowing them to overcome the tumor’s immune suppression and mount a robust anti-cancer response. SCC tumors are particularly good candidates for this therapy due to their high tumor mutational burden, which makes them highly recognizable to the newly activated immune cells. The reactivated T-cells are then free to infiltrate the tumor microenvironment, identify the cancer cells, and destroy them.
Approved Immunotherapy Agents and Specific SCC Applications
The development of immune checkpoint inhibitors has established a new standard of care for patients with advanced Squamous Cell Carcinoma, particularly in cases where the disease is locally advanced, recurrent, or metastatic. The primary drugs used in this setting target the PD-1/PD-L1 axis.
Cemiplimab (Libtayo), an anti-PD-1 monoclonal antibody, was the first agent specifically approved for advanced cutaneous SCC (CSCC). It is indicated for patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or radiation therapy. Cemiplimab is also used as adjuvant treatment after surgery and radiation in high-risk CSCC to reduce the chance of the cancer returning.
Pembrolizumab (Keytruda) is another anti-PD-1 inhibitor approved for the treatment of CSCC that is recurrent or metastatic and cannot be cured by surgery or radiation. The use of Pembrolizumab also extends to Head and Neck Squamous Cell Carcinoma (HNSCC). For locally advanced HNSCC, Pembrolizumab is approved for use both before and after surgery in combination with other standard therapies.
The application of these therapies reflects the diverse origins of SCC, necessitating distinct treatment strategies depending on the site of the primary tumor. SCC of the skin (CSCC) and SCC of the head and neck (HNSCC) are treated with the same class of drugs, but the specific indications and combination regimens differ based on clinical trial data. Other checkpoint inhibitors, such as Nivolumab, are approved for use in recurrent or metastatic HNSCC, often after a patient has progressed on platinum-based chemotherapy.
Treatment Administration and Expected Patient Outcomes
Immunotherapy for SCC is typically administered intravenously (IV) through a controlled infusion over a set period in an outpatient setting. The frequency of these infusions varies depending on the specific agent used, but common schedules include receiving treatment every two, three, or six weeks. Treatment is generally continued for a specified duration or as long as the therapy remains effective and the patient can tolerate the side effects.
Response to immunotherapy is measured by the objective response rate (ORR), which is the percentage of patients experiencing a measurable reduction in tumor size. In advanced CSCC, clinical trials have shown objective response rates in the range of approximately 40% to 50%.
A defining characteristic of successful immunotherapy is the concept of durable response, meaning the tumor reduction lasts for a long period. In many responders, these benefits can persist for six months or longer, and in some cases, the tumor may disappear completely, known as a complete response. Factors like a high tumor mutational burden in CSCC are associated with a greater likelihood of response.
While immunotherapy does not work for everyone, those who do respond often experience a prolonged and substantial benefit that was rarely seen with previous systemic therapies. The goal of treatment is to achieve a long-lasting control of the disease, effectively turning a progressive cancer into a manageable chronic condition.
Managing Immune-Related Side Effects
A unique aspect of checkpoint inhibitor therapy is the potential for immune-related adverse events (irAEs), resulting from the activated immune system attacking healthy tissues. These side effects differ from those caused by traditional chemotherapy and can affect almost any organ system. Although the overall incidence of severe irAEs is relatively low, their potential for widespread systemic damage requires specialized management.
Commonly reported irAEs involve inflammation of organs such as:
- The colon (colitis)
- The lungs (pneumonitis)
- The liver (hepatitis)
- Endocrine glands (thyroiditis)
Skin reactions, such as a rash or itching, are among the most frequent, often appearing early in the course of treatment. The onset of these adverse events can occur at any point during therapy, and sometimes even months after the treatment has been stopped.
Effective management relies on the prompt recognition and grading of the severity of the symptoms. For moderate (Grade 2) or severe (Grade 3 or 4) irAEs, the standard course of action involves temporarily or permanently stopping the immunotherapy. The primary treatment for suppressing the overactive immune response is the administration of corticosteroids.
For severe symptoms, high-dose intravenous steroids (e.g., 1 to 2 mg/kg per day of prednisone equivalent) are initiated immediately. Once the symptoms have resolved to a mild or manageable level, the steroid dose is slowly reduced over a period of four to six weeks to prevent the irAE from flaring up again. In cases that do not improve with steroids, other immunosuppressive agents may be required.