Annually, more than 550,000 new cases of oral, head, and neck cancer are identified globally. Head and neck cancer demands serious attention due to its potential severity, necessitating prompt diagnosis and effective treatment strategies. These cancers commonly metastasize to neck lymph nodes, increasing the risk of systemic spread. Early-stage treatment minimizes post-treatment disfigurement and functional impairment, emphasizing the importance of timely intervention.
In recent years, immunotherapy has emerged as a promising avenue in the treatment of head and neck cancer. This innovative approach offers new hope in addressing advanced stages of head and neck cancer, contributing to a more comprehensive and personalized treatment landscape.
What is Head and Neck Cancer?
Head and neck cancer refers to a group of malignant tumors that develop in or around the throat, larynx, nose, sinuses, and mouth. The predominant type is squamous cell carcinoma, originating in flat squamous cells that form the surface layer of head and neck structures.
Below this surface lies the mucosa, a moist tissue layer. Carcinoma confined to the squamous cell layer is termed carcinoma in situ, while invasive squamous cell carcinoma denotes cancer extending into deeper tissues. When the primary cancer site is unidentified, it is categorized as cancer of unknown primary. Salivary gland-originating tumors are classified as adenocarcinomas, adenoid cystic carcinomas, or mucoepidermoid carcinomas.
Types of Head and Neck Cancer
There are 6 major types of head and neck cancer:
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Oral Cavity Cancer
Oral cavity cancer affects the lips, tongue, gums, and the lining of the mouth. Common risk factors include tobacco use, excessive alcohol consumption, and infection with the human papillomavirus (HPV). Symptoms may manifest as persistent mouth sores, swelling, or changes in voice. Early detection is crucial for successful treatment, often involving surgery, radiation therapy, or a combination of both.
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Pharyngeal Cancer
Pharyngeal cancer encompasses three regions: nasopharynx, oropharynx, and hypopharynx. Linked to smoking, alcohol use, and HPV infection, this cancer presents symptoms such as difficulty swallowing, persistent sore throat, and ear pain. Treatment modalities depend on the specific region affected and may include surgery, radiation, or chemotherapy.
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Laryngeal Cancer
Laryngeal cancer affects the voice box (larynx), crucial for speech and breathing. Major risk factors include smoking and excessive alcohol consumption. Symptoms may include hoarseness, persistent cough, and difficulty breathing. Treatment options range from surgery to radiation therapy, often tailored to the cancer’s stage and location.
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Paranasal Sinus and Nasal Cavity Cancer
Paranasal sinus and nasal cavity cancer develop in the sinuses and nasal passages. Frequently diagnosed at an advanced stage due to late symptom manifestation, symptoms may include nasal congestion, facial pain, and recurrent sinus infections. Treatment involves surgery, radiation, and sometimes chemotherapy.
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Salivary Gland Cancer
Salivary gland cancer originates in the glands responsible for saliva production. Different types include mucoepidermoid carcinoma and adenoid cystic carcinoma. Symptoms may include swelling, pain, or facial nerve paralysis. Treatment varies based on the type and stage of cancer, often involving surgery and radiation therapy.
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Thyroid Cancer
Although located in the neck, thyroid cancer is often considered separately. Risk factors include radiation exposure and family history. Symptoms may involve a lump in the neck, difficulty swallowing, or changes in voice. Treatment includes surgery, radioactive iodine therapy, and, in some cases, hormone therapy.
Understanding the unique characteristics of each head and neck cancer is crucial for effective diagnosis and tailored treatment approaches.
What is Immunotherapy?
Immunotherapy is a type of medical treatment that harnesses and enhances the body’s own immune system to combat diseases, particularly cancer. Unlike traditional treatments like chemotherapy or radiation, which directly target cancer cells, immunotherapy stimulates the immune system, enabling it to recognize and destroy cancer cells more effectively.
This approach includes various techniques, such as using immune checkpoint inhibitors, adoptive cell transfer, or therapeutic vaccines. Immunotherapy has shown promise in treating different types of cancers and is at the forefront of advancing personalized and targeted therapies in the field of oncology.
What Is Immunotherapy for Head and Neck Cancer?
Immunotherapy, a cancer treatment method, enhances the body’s immune system to target and eliminate cancer cells. This approach encompasses various modalities such as vaccines, immune-boosting drugs, and therapeutic immune cells. In the context of head and neck cancer, when diagnosed, the oncologist assesses whether incorporating immunotherapy into the treatment plan is appropriate for the patient. Additionally, the possibility of participating in clinical trials is explored as a potential option.
Upon a head and neck cancer diagnosis, the oncologist tailors the treatment strategy based on the individual’s condition. This may involve the administration of vaccines designed to stimulate the immune response, medications that directly fortify the immune system, or the infusion of specialized immune cells to combat the cancer. The decision-making process considers the patient’s specific circumstances, and the oncologist may recommend participation in clinical trials to explore innovative approaches. The goal is to optimize the overall treatment plan and enhance therapeutic outcomes for individuals facing head and neck cancer.
Checkpoint Inhibitors in Head and Neck Cancer Treatment
Head and Neck Squamous Cell Carcinoma (HNSCC) ranks as the 6th most prevalent cancer globally, typically manifesting as locally advanced disease. Despite aggressive multimodal treatments involving surgery, radiotherapy, chemotherapy, or EGFR inhibition where applicable, there is a substantial 50% recurrence rate. Advances in comprehending cancer biology and the intricate interactions within the tumor microenvironment have sparked growing interest in the potential of immunomodulating agents for managing HNSCC.
In this context, immune checkpoint inhibitors have emerged as promising contenders. These agents aim to disrupt the inhibitory interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1. Notably, pembrolizumab and nivolumab garnered FDA approval in 2016, showcasing durable improvements in patient outcomes, particularly in advanced/metastatic HNSCC.
The current landscape includes a plethora of ongoing clinical trials investigating checkpoint inhibitors, both as standalone treatments and in combination with established modalities like chemotherapy and radiotherapy. Additionally, these inhibitors are being explored alongside novel immune modulators, not only in advanced/metastatic HNSCC but also in neoadjuvant or adjuvant settings.
As these studies conclude and results accumulate, the role of immunotherapy agents in HNSCC treatment strategies may undergo transformation. The evolving landscape could see increased biomarker selection leading to personalized therapy, a pivotal shift aimed at enhancing patient outcomes. The integration of immunomodulating agents into the broader therapeutic arsenal for HNSCC holds promise, with the potential to revolutionize the approach to this challenging cancer.
Head and neck cancer encompasses a range of malignancies originating in the paranasal sinuses, nasal cavity, oral cavity, pharynx, and larynx. Annually, Europe witnesses around 139,000 new cases of head and neck cancer, with squamous cell carcinoma (HNSCC) accounting for a significant 90% of these cases. Well-established risk factors, including smoking and alcohol consumption, have historically been linked to the development of HNSCC.
A noteworthy transformation has emerged with the recognition of human papillomavirus (HPV) as a substantial driver for a considerable percentage of oropharyngeal squamous cell carcinomas. Increasingly, HPV-associated HNSCC is identified as a unique clinical entity, distinguished by a more optimistic prognosis compared to its non-HPV associated counterpart. This evolving comprehension underscores the imperative for nuanced approaches in the diagnosis and management of head and neck cancers, acknowledging the diverse etiological factors shaping their onset.
The approval by the FDA in 2016 of monoclonal antibodies targeting Programmed Death-1 (PD-1), namely pembrolizumab and nivolumab, marked a significant breakthrough in the treatment landscape for Head and Neck Squamous Cell Carcinoma (HNSCC). This milestone ushered in a new era for a patient demographic with a historical recurrence rate of 50%, despite undergoing aggressive multimodal treatments, which include surgery, radiotherapy, chemotherapy, and, when suitable, EGFR inhibition.
Maintaining a healthy immune system is crucial to prevent the development of cancer. When cancer cells want to grow and spread, they find ways to hide from the immune system. Immunotherapy is a treatment that believes our immune system can be activated to recognize and fight against these hidden cancer cells.
For this to work, special immune cells called T-lymphocytes need to get into the tumor and respond effectively. In various cancers, including Head and Neck Squamous Cell Carcinoma (HNSCC), having more of certain types of immune cells, like CD3+, CD8+, and FOXP3+, is linked to better outcomes. Specifically, having more CD8+ “effector” T-cells and a good balance with FOXP3+ regulatory T-cells (Tregs) is connected to a better chance of recovery. Tregs usually suppress immune responses, and their presence in head and neck cancers might help the cancer hide from the immune system. However, we still need to learn more because while Tregs are linked to less survival in some cancers, they seem to have a positive impact in others like ovarian cancer, colorectal cancer, and lymphoma.
Some cancers have tricks to avoid the immune effects of T-cells by keeping them out of the tumor area. However, when it comes to Head and Neck Squamous Cell Carcinoma (HNSCC), it’s one of the cancer types where the immune system is present in the tumor. This suggests that there are other factors at play, and the movement and activity of T-cells are influenced by the tumor itself.
In HNSCC, there are several ways the tumor tries to prevent T-cells from working:
The tumor can have issues or changes in showing certain signals (human leukocyte antigen or HLA class I molecules) to T-cells. It can also produce too much of some signals, causing T-cells to ignore them.
The tumor may release substances that calm down the immune system, such as IL-10, IL-6, and TGF-β.
Certain switches inside the tumor cells, like STAT3 and NF-kB, can be turned on in the wrong way. These switches are connected to the signals from IL-6 and TGF-β.
Understanding these ways the tumor tries to avoid the immune system helps researchers find better ways to treat HNSCC.
To prevent the immune system from mistakenly attacking the body, there are safety checkpoints on the surface of immune cells. Activating a T-cell response is like finding the right balance between molecules that say “go” and others that say “stop.”
For Head and Neck Squamous Cell Carcinoma (HNSCC), there are special drugs that block the “stop” signals, which are like roadblocks. These drugs target receptors like Cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4), Programmed death-1 (PD-1), or Lymphocyte activation gene-3 (LAG-3) and their signals. On the flip side, there are also drugs that act like the “go” signals, boosting the immune response to fight against tumor cells. Both of these approaches aim for the same thing: making the immune response against the tumor stronger.
PD-1/PD-L1 Axis: PD-1 is like a traffic controller for our immune system and is found on certain immune cells. When it’s activated, it can slow down the immune response. In cancers like Head and Neck Squamous Cell Carcinoma (HNSCC), cancer cells can use PD-1 to escape from the immune system by turning off the T-cells. Nivolumab and pembrolizumab are special drugs that block this PD-1 and help the immune system fight against the cancer.
Nivolumab: In a big study (CheckMate 141), nivolumab was compared with standard treatments for patients with HNSCC that came back after platinum-based therapy. The results showed that nivolumab worked better, with more patients having a response (getting better) and living longer. Side effects were also less with nivolumab.
Pembrolizumab: Another drug, pembrolizumab, was tested in patients with recurrent or metastatic HNSCC. It showed promising results in a study called KEYNOTE-012, with patients responding well to the treatment. The FDA approved pembrolizumab based on these results. There’s an ongoing larger study (KEYNOTE-040) to learn more about how well it works compared to standard treatments.
Other Drugs: Apart from nivolumab and pembrolizumab, there are more drugs being tested, like durvalumab, atezolizumab, and avelumab, to see if they can also help the immune system fight against HNSCC. Researchers are hopeful about these drugs and continue to study their effectiveness.
Combination Checkpoint Inhibition
Recent findings suggest that when we try to stop the PD-1/PD-L1 axis in cancer, some other immune checkpoints step up, making it tricky. To tackle this, scientists are looking into using a mix of checkpoint inhibitors (CPI), a strategy that has worked well in other cancers. More and more of these checkpoint inhibitors, which can either boost or calm down the immune system, are being tested in Head and Neck Squamous Cell Carcinoma (HNSCC).
CTLA-4 is like a brake for our immune system and is found on certain immune cells. When it’s active, it slows down the immune response. Scientists found that if they block CTLA-4, it boosts the immune system, helping it fight cancer better. Combining this with stopping PD-1/PD-L1 has shown improved results in cancers like melanoma. Now, they’re exploring if this combo can work in Head and Neck Cancer too.
DENVAX: Dendritic Cell-Based Cancer Immunotherapy for Head and Neck Cancer
Dendritic cell-based cancer immunotherapy is an innovative approach that leverages the unique capabilities of dendritic cells (DCs) to stimulate the immune system and enhance its response against cancer, including head and neck cancer. Here’s how dendritic cell-based immunotherapy works for head and neck cancer:
Dendritic Cells (DCs): Dendritic cells are a type of immune cell with a crucial role in presenting antigens to other immune cells, particularly T cells. They act as messengers that capture, process, and present pieces of cancer cells (antigens) to activate the immune system.
Collection of Dendritic Cells: The first step in dendritic cell-based immunotherapy involves collecting dendritic cells from the patient’s blood or, in some cases, from the tumor itself.
Dendritic Cell Maturation: The isolated dendritic cells are then matured and activated in the laboratory. This process is crucial for enhancing the dendritic cells’ ability to stimulate an immune response.
Loading Dendritic Cells with Antigens: Cancer-specific antigens are introduced to the matured dendritic cells. These antigens can be obtained from the patient’s own tumor tissue or synthesized versions of tumor-specific proteins. The goal is to train dendritic cells to recognize and present these cancer-specific antigens.
Dendritic Cell Vaccination: The now antigen-loaded and activated dendritic cells are reintroduced into the patient’s body. This can be done through injections, similar to a vaccine. The dendritic cells act as teachers, instructing the immune system to recognize and attack the cancer cells.
Immune System Activation: Once inside the body, the matured dendritic cells present the cancer antigens to T cells, specifically activating cytotoxic T cells. Cytotoxic T cells are the immune cells responsible for directly attacking and destroying cancer cells.
Targeting Cancer Cells: Activated cytotoxic T cells, now armed with the knowledge of the specific cancer antigens, seek out and attack the cancer cells in the patient’s body. This targeted immune response aims to eliminate the cancer cells while sparing healthy tissues.
Memory Response: Dendritic cell-based immunotherapy can induce a memory response in the immune system. This means that even after the initial treatment, the immune system retains the ability to recognize and respond to cancer cells, providing potential long-term protection against cancer recurrence.
Dendritic cell-based cancer immunotherapy holds promise as a personalized and targeted treatment for head and neck cancer. It is an area of active research, and ongoing clinical trials aim to optimize the effectiveness of this approach, explore its combination with other therapies, and further refine its application in the treatment landscape for head and neck cancer patients.
Immunotherapy for Head and Neck Cancer: What to Expect During Treatment
If your doctor recommends immunotherapy for head and neck cancer, you’ll get it through an IV at an outpatient infusion center. A cancer nurse or doctor will take care of you during the treatment, and they’ll let you know how long each session will be.
Before each treatment, you might need some blood work to make sure your body is handling the treatment well. Immunotherapy is given in cycles, with breaks in between to let your body rest and recover. Your doctor will give you an idea of how long you’ll be receiving immunotherapy when you start the treatment.
During the treatment, you’ll be in a comfortable setting, and the medical team will monitor you closely. The sessions may vary in length, so your nurse will provide details about the duration.
It’s important to follow your doctor’s advice and attend all scheduled treatments to maximize the effectiveness of immunotherapy. If you have any concerns or questions, feel free to discuss them with your healthcare team. They are there to support you throughout the process and ensure you have a clear understanding of what to expect during your immunotherapy for head and neck cancer.
General Side Effects of Immunotherapy For Head and Neck Cancer
Have a look at some general side-effects of Immunotherapy for head and neck cancer:
Common Side Effects: General side effects of immunotherapy for head and neck cancer include fatigue, nausea, and decreased appetite.
Individual Variability: Patients may experience these side effects to varying degrees. Some may have little to no change in appetite or energy, while others may face significant fatigue and reduced appetite.
Consistent Fatigue: Most patients, however, tend to experience some level of fatigue during the course of treatment.
Milder Nausea: Compared to traditional chemotherapy medications like Cisplatin, commonly used in head and neck cancer, immunotherapy typically causes less severe nausea.
Allergic Reactions: As with other cancer medications, there is a possibility of allergic reactions during the drug infusion process.
Patient Specificity: Every patient reacts differently, so the intensity and occurrence of side effects can vary.
Energy Levels: Fatigue levels may range from mild to significant, impacting daily energy levels for some patients.
Appetite Changes: While some may notice a decrease in appetite, others may not experience significant changes in their eating habits.
Nausea Comparison: Immunotherapy-induced nausea is generally less pronounced compared to traditional chemotherapy medications.
Allergic Responses: It’s important to be aware of the potential for allergic reactions and promptly communicate any concerns to the healthcare team during infusion sessions.
Immune-Related Adverse Effects of Immunotherapy For Head and Neck Cancer
Immune-related adverse effects can impact various body parts, with common areas being the glands, lungs, liver, skin, and colon. These events can occur at any point during treatment, emphasizing the need for ongoing monitoring. For mild events, treatment may involve a pause in therapy until side effects resolve. Moderate or severe events may require cessation of treatment, with the introduction of immunosuppressive medications like steroids to curb the immune response. Most adverse events can be effectively managed with immunosuppressive medications.
After resolution, and completion of steroid treatment, restarting immunotherapy may be considered based on the initial severity. Due to the potential seriousness of these events, it’s crucial for patients to promptly report any new symptoms. Physicians will assess symptoms, ruling out non-immune causes, as there isn’t a single diagnostic test for immune-related adverse events. Staying vigilant and open in communication helps ensure timely intervention and management.
Final Note
Immunotherapy is an evolving and promising avenue in the treatment of head and neck cancer. With its focus on harnessing the body’s immune system to combat cancer, it brings hope for more effective and personalized treatments. Dendritic cell-based immunotherapy, a novel approach, shows potential in stimulating immune responses. Despite side effects, ongoing research aims to optimize immunotherapy, offering a beacon of progress in the challenging landscape of head and neck cancer treatment. It’s essential for patients to communicate openly with their healthcare teams to ensure personalized care and maximize the benefits of these innovative treatments.
