Mechanisms of Immunotherapy in HNSCC

Transcript:Robert L. Ferris, MD, PhD: Cetuximab is a monoclonal antibody. It was developed to block the epidermal growth factor receptor, or EGFR. The higher the level of EGFR, the worse the clinical outcome. Therefore, it made sense to use a blocking antibody to inhibit EGFR since high levels were a poor prognostic factor. Subsequent to a large experience with cetuximab, it became clear that the benefit from cetuximab is not always seen just because there is a high amount of EGFR around that is expressed by the tumor cell. This led to a large amount of research looking at the potential immune effects, otherwise known as antibody-dependent cellular cytotoxicity (or ADCC), which is a potential mechanism of action for cetuximab to not only inhibit EGFR, but potentially to stimulate the immune system against the cancer cell.

Because some immune mechanism of action appears to be responsible for the effect of the clinical benefit from cetuximab, this led to the concept that head and neck cancer might be an immunogenic or immune-responsive type of disease. Later work demonstrated that other immune receptors, such as the checkpoint receptors PD-1 and CTLA4, were expressed on lymphocytes from head and neck cancer patients. This led to additional work and research showing that blocking antibodies against PD-1 or CTLA4 could be therapeutically effective and provide an immunotherapeutic strategy for head and neck cancer.

Nabil F. Saba, MD: Head and neck cancer represents a group of complex malignancies that have the characteristic of immune suppression. And traditionally, we think of head and neck cancer risk factors in the HPV-negative group as mostly alcohol-related and tobacco-related. But we’re realizing that the reason these cancer cells are surviving goes beyond those known risk factors, and cancer cells are able to transform and become heterogenous in their characteristics. By doing that, they can escape the immune system and cause immune suppression. And so, the interaction between the tumor microenvironment and a subset of T-lymphocytes basically results in the immune suppression that we’re talking about. Now, patients who have a history of immune suppression, or diseases that lead to immune suppression, are also at high risk for developing head and neck cancer and usually have a worse prognosis when they develop this disease.

So, on one hand, we have this aspect of head and neck cancer, which is basically HPV-negative. We also have the HPV-positive disease, and there we know that tonsil cancer cells that are infected with the HPV virus tend to create an immune-privileged site and also escape the immune system through the PD-1, PD-L1 access. And so, when it comes to immune therapy, we have, on one hand, a disease that is heterogenous, is linked to environmental carcinogens, and leads to immune suppression, and on the other hand, a virally induced tumor. On both counts, immune therapy stands to make a major difference in the outcome and treatment for head and neck cancer, as it has already shown.

Patients with autoimmune diseases usually have chronic immune suppression. Patients with other types of diseases, too, including chronic steroid use and certain genetic inherited diseases, such as Fanconi anemia, may be at some increased risk, as well, of developing tumors, including head and neck cancer. And these patients, in general, have a worse prognosis. We think it’s because of the immune suppression they have, but also because these tumors may be biologically more aggressive than a patient who does not have these other risk factors.

Transcript Edited for Clarity