Checkpoint Inhibitors in HNSCC

Insights From: Ezra Cohen, MD, Moores Cancer Center; UC San Diego Health; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center


Ezra Cohen, MD:
When we think about head and neck cancer and the underlying biology, we have to consider that there are really 2 distinct etiologies that we recognize. The traditional is carcinogen-induced, tobacco-related head and neck cancer, now being referred to as HPV-negative. This is characterized by a slightly higher mutational burden. The mutations tend to be in tumor suppressor genes like p53, p16, and FAT1, which tends to be more aggressive—it tends to be less responsive to therapy, and the prognosis, unfortunately, is worse with the carcinogen-induced head and neck cancer.

The converse is virally induced, and that is HPV-driven by the virus, primarily by the viral genes of E6 or E7. But, not exclusively, we’re recognizing that the other viral genes also play an important role in the etiology. We also recognize that it has an appreciable mutational burden, but not as high as in the HPV-negative patients. However, because it’s virally induced, we often see a robust immune infiltrate characterized by T-cells and macrophages. HPV-positive cancers tend to have a better prognosis. They tend to respond better to therapy, and they have a higher cure rate.

Jared Weiss, MD: We have 2 very different kinds of head and neck cancers, biologically, and immune checkpoint inhibitors seem to work in both of them. Why? Well, one of these subtypes is the smoking-driven head and neck cancers. These are cancers with high mutational burdens and high neoantigen burdens, and they are very immunogenic. Some, biologically, have used the word “inflamed” to describe them. These are very inflammatory cancers—a lot going on, very mucked-up perturbed milieu, and, scientifically, a high degree of interferon-gamma signaling going on there. It’s more like the melanoma example of the high mutational burden—high neoantigen. And there the checkpoint inhibitors certainly work.

What about the other half? The other half, or other portion, are the virally driven cancers, particularly the HPV-driven oropharynx cancers. And here it’s notable that this is a virally induced cancer. By its nature, a virally infected cell is going to have certain neoantigens. Our immune system exists in everyday life to fight infections. And so, there’s activity there as well. You have 2 very different biologic groups that seem to both benefit from the efficacy of the drugs. Both of these subtypes are T-cell invaded.

Ezra Cohen, MD: When we further look at HPV-positive cancers, and we begin to ask questions around the tumor microenvironment—especially with respect to immune markers—we quickly recognize that most HPV-positive cancers express high levels of PD-L1. That expression can be on tumor cells or it can be on the tumor infiltrating immune cells, especially macrophages. About two-thirds to even three-quarters of HPV-positive cancers will have some degree of expression of PD-L1, suggesting that they may be good candidates for therapy with PD-L1 or PD-1 antibodies.

Transcript Edited for Clarity
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