Immunotherapy for Virally Induced vs High-Mutation Burden HNSCC

Transcript:Ezra Cohen, MD: We’ve come to recognize that immunotherapy does have a role in squamous cell carcinoma of the head and neck, and the best examples of that are, of course, the anti—PD-1 or the anti–PD-L1 antibodies. Let’s pause for a moment and think about the mechanism of action of these drugs and relate that to both virally induced and nonviral, or tobacco-induced, cancer. We’ll get back to this question of mutational load or mutational burden and how it plays a role in the mechanism of these drugs.

Remember that the immune system is essentially designed to eliminate pathogens. And so, what it was designed to do was detect when something foreign entered our body, eliminate that foreign substance, and then dampen down very quickly. So, for instance, if we had a bacterial infection, the immune system would recognize it, the immune system would respond to it, and then the immune system would shut itself off. If it didn’t shut itself off, that would be very bad for the host. And so, all these mechanisms are physiologic. What cancer does is it exploits these normal physiologic mechanisms in order to survive. And what we’ve come to recognize is that one of the major mechanisms is these breaks in the system. Again, naturally occurring receptors or ligands are supposed to shut the immune system down after it has responded appropriately to a pathogen.

One of the major mechanisms is PD-1 or PD-L1. We call these negative regulators or negative checkpoints. And what we’ve come to recognize is that when we block that interaction, when we block that checkpoint, all of a sudden the T cells that have recognized the cancer can begin to activate and eliminate tumor cells. That is a fairly simplistic review of how anti—PD-1 or anti–PD-L1 antibodies work. But now, let’s talk in the context of squamous cell carcinoma of the head and neck.

What’s interesting is that, of course, HPV is a virus. And HPV-positive cancers often have evidence of an immune response. What I mean by that is these cancers are often infiltrated with CD8 cytotoxic T cells, they often express high levels of PD-L1. But at the same time, they also have the natural mechanisms that are turning off the immune response, including T-regulatory cells—so these negative regulators—and including tumor-associated macrophages that express high levels of PD-L1. And so, with that information at hand, we were very excited to apply the anti—PD-1, anti–PD-L1 antibodies to patients with HPV-positive head and neck cancer. And in fact, what we saw was that these patients responded, and when they responded, they often did very well.

For patients who don’t have virally related head and neck cancer, their cancer is often related to tobacco. What’s interesting there is that the same drugs—nivolumab, pembrolizumab—work in HPV-negative cancers as well. And we think the reason that they work there is because some of these cancers have been recognized by the immune system because of the mutations that are inherent in those cancers. Again, going back to basic immunology, the immune system is designed to recognize something different. In the case of cancer, it’s mutations or what we call neoantigens—antigens that are presented on a cancer cell that are completely foreign—that are completely different to the immune system, which recognizes those cells that have those neoantigens and eliminate those cells. And, again, the same physiologic mechanisms come into play. The cancer has found a way to avoid the elimination by the immune system, usually by some sort of immunosuppressive mechanism, often by a checkpoint. And if we interfere with that negative mechanism—that is, we take the brakes off—all of a sudden the T cells do their job and they eliminate the cancer.

For HPV-positive, it’s maybe often related to the fact that its core is a viral infection. For HPV-negative, or tobacco-associated, it’s related to the fact that there is a high mutational burden and there are neoantigens being presented to the immune system.

Transcript Edited for Clarity