Research News

Content adapted from Cleveland Clinic Cancer Advances

Director of Head and Neck Research and surgical oncologist at Cleveland Clinic, Natalie Silver, MD, MS, joins the Cancer Advances podcast to talk about head and neck cancers and the treatment barriers we are trying to overcome. Listen as Dr. Silver explains how she is trying to bridge the gap between the clinical and translational research with her work on vaccines.

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma programs. Today, I'm happy to be joined by Dr. Natalie Silver, Director of Head and Neck Research at Cleveland Clinic. She's here today to talk to us about novel vaccine research in head and neck cancer. Welcome, Natalie.

Natalie Silver, MD, MS: Hey, thank you so much for having me today.

Dale Shepard, MD, PhD: Absolutely. Maybe just start, give us a little bit of an idea. What's your role here at Cleveland Clinic? What do you do?

Natalie Silver, MD, MS: I am a Surgeon-Scientist. I spend a lot of time over in the Lerner Research Institute and the Center for Immunotherapy & Precision Immuno-Oncology. I'm 80% research and 20% clinical. I'm also a Head and Neck Surgical Oncologist. I have a practice, primarily out of Taussig, but also in the operating room, as well, doing head and neck cancer cases.

Then, I run a translational research lab inside the Lerner Research Institute, investigating novel therapeutics for head and neck cancer, as well as the role of the oral microbiome in head and neck cancer and tumor progression. I have the role as Director of Head and Neck Cancer at the Head & Neck Institute. In that role, I'm really trying to bridge the gap between the clinical aspects of what we do, and the basic science and translational research.

Dale Shepard, MD, PhD: Very good. We have a wide range of people who may be listening in, so let's start really basic. When we say head and neck cancer, that's, of course, not a body organ. We think of an organ, like a lung cancer. Remind people, what does head and neck cancer entail?

Natalie Silver, MD, MS: Sure. Head and neck cancer is primarily mucosal lining cancers of the head and neck. The most common cancer that we treat is squamous cell carcinoma. Those are cancers that affect the larynx, the tonsil, the back of the tongue, the front of the tongue. That's a main group of head and neck cancers, but head and neck cancer also encompasses salivary gland cancer and other endocrine cancers, such as thyroid cancer. Nasopharyngeal cancer is also another type of head and neck cancer that's treated a little bit differently than some of the other ones.

It's a wide variety of different cancers that are primarily from the skull base to the clavicle, is what we take care of. Of course, as you know, there's sarcomas there, as well. There's all different kinds of tumors that can come up in the head and neck and that's what we primarily take care of. When you generally think about head and neck cancer, the most common, by far, excluding thyroid, is the squamous cell cancers of the upper aerodigestive tract.

Dale Shepard, MD, PhD: All right. Excellent. When we think about the fact that you spend most of your days researching new and better ways to treat cancer, I guess that would suppose that we have limitations on what we're currently doing. What are the way we treat now and what are the barriers to effective treatment that we're trying to overcome?

Natalie Silver, MD, MS: Absolutely. Within the squamous cell cancers of the upper aerodigestive tract, the big diversion is the HPV viral-related cancers and then the HPV-negative cancers. The state of HPV-positive cancer right now, the patients have a significantly better outcome. HPV viral-associated cancers primarily affect the tonsil and tongue base. There have been a lot of advances, innovations, and deintensification of treatment for these patients. The challenge we face with that cohort is really just, we know that they're going to do well. They have about an 85 to 90% overall survival at five years, which is excellent for any cancer. The goal is that these are primarily young-ish white men, that's the common demographic, that will have a long life after their cancer treatment.

There are a lot of ways, that we're trying as a field, to deintensify treatment, whether it's deintensification of radiation, adding surgery to then decrease the postoperative radiation dose, or adding neoadjuvant treatments. That's the primary focus of that part of our field and how we treat it.

The major challenge that I see is really in these HPV-negative patients. These are typical patients that have disease that are caused by smoking and/or drinking. However, there's a larger population that's coming up, that have smoking-unrelated cancers, and they still have a pretty poor prognosis after five years, about 40% with advanced, say, oral cancer.

We primarily treat those patients with major surgery. It's primarily surgery, and that involves often removing a significant portion of the oral cavity or removing the larynx. A very big surgery, followed by six weeks of chemoradiation, path-based guided treatment.

Chemo is sometimes added, depending on the pathologic features, but it's a very long, difficult course for our patients. The survival isn't great. We give them the biggest dose of radiation. We give them the biggest surgery we can possibly give a person, and a lot of them still recur or they fail distantly. We're obviously not doing the best we can for our patients.

I see a need in that area. That's where I focus a lot of my research, is to try to find better strategies for patients that either recur or ways to help patients with that type of HPV-negative cancer.

Dale Shepard, MD, PhD: All right. We're going to be talking about vaccines and that's certainly a way to stimulate an immune response. Most of the time, when we talk to patients and they mention immunotherapy, they're thinking about checkpoint inhibitors and things like that. Maybe just briefly tell us about the role of checkpoint inhibitors in head and neck cancers. Then, we're going to move more toward vaccines.

Natalie Silver, MD, MS: Yeah. Right now, checkpoint inhibitors are approved for first-line recurrent metastatic patients. If you have had prior chemo or not, if you have failed primary treatment and have recurrence... In head and neck, a lot of patients recur in the lungs distantly, sometimes local, regionally, if it's not resectable, then treatment with pembrolizumab is indicated.

There have been a lot of studies that have shown benefit to this population with durable responses. A large amount still do not respond, but there is encouraging data in that there are obviously some solid tumors in our spectrum that don't respond hardly at all to checkpoint inhibitors. It's been very encouraging that the head and neck cancer patients do have about a 20% response rate, which is not great and can be improved upon, but it's definitely better than the 1 to 2% two-year survival after recurrent metastatic disease, with the standard chemotherapy regimens.

There's a lot of interest and clinical trial efforts looking at combinations of immunotherapies, as well as different ways to treat these patients using some type of immunotherapy.

Dale Shepard, MD, PhD: When we think about a lot of the work you do is related to vaccines, and certainly a success story from a vaccine standpoint is with the HPV-positive cancers in terms of prevention, but tell us a little bit about therapeutic vaccines, as well.

Natalie Silver, MD, MS: Great. That's exactly true. There's been a great success with the HPV vaccine and that is, of course, a prophylactic vaccine, a preventative vaccine. You can get your kids vaccinated. It has already shown decreases in incidents of cervical cancer and other cancers.

With therapeutic vaccines, though, as we know, this is something that needs to be administered pretty quickly. Preventative vaccines, they're often administered in several doses. It takes a while for the immune system to develop immunity towards an antigen. But for these types of therapeutic vaccines, the idea is really that it is an immunotherapy, an anti-tumor agent.

Our formulation is delivered intravenously. It's very powerful, compared to some of the other mRNA vaccine platforms that do not administer intravenously. Ours is delivered intravenously, so that we can elicit a very strong immune response against a tumor. That's one of the main differences between a preventative vaccine and a therapeutic vaccine.

Dale Shepard, MD, PhD: What kind of work are we doing currently to develop these therapeutic vaccines?

Natalie Silver, MD, MS: There are a lot of companies that are working on therapeutic vaccine development, but my research and my platform, it was developed at the University of Florida, where I came from just eight months ago. I've been at Cleveland Clinic. I worked on this for several years with my partner, Elias Sayour, who was a pediatric neuro-oncologist at the University of Florida. He had been working on this platform for about 10-plus years. I joined him when I joined the faculty at the University of Florida.

He has been developing mRNA vaccines, therapeutic mRNA vaccines for pediatric brain cancer, specifically, and adult brain cancer. When I joined him, I started investigating this platform for head and neck cancers. The platform that we have is actually a personalized or tumor-derived vaccine. We actually take a biopsy from a patient or from a tumor resection, depending on what happens first.

We actually create the mRNA from the tumor, itself. We're able to basically represent the transcriptome. We're basically representing everything, all the mRNA that is made in a tumor. We're able to amplify that. We do that in the lab, we amplify that. Then, we complex it with a liposome, a nanoparticle, and deliver it intravenously to the patient.

Our formulation has several patents and has a formulation in which it enables us to deliver a very high payload of mRNA to the patient. What that does, is the mRNA with the nanoparticle, or the nanoliposome, essentially transects immune cells, dendritic cells, for antigen presentation. Now, our formulation, we don't know exactly what antigens we're actually presenting. They're tumor antigens, though. There are different ways to make these mRNA formulations, including we can do targeting. We can target, say, E67. Or if we have a known fusion, one of the things we're actually looking at is possibly sarcomas, rhabdosarcomas, that have known fusions that are pretty antigenic.

There are ways that we can have a specific target, but the formulation that we actually have IND approval to use in humans is a tumor-derived formula. We have found that that's been highly efficacious. A lot of people say, "Why don't you target?" But our preliminary data is very solid, looking at all of the - using the formulation we have. The idea that my mentor used to say is, "We're not smart enough to out-trick the tumor yet." We deliver all the possible scenarios to the immune system. The immune system can figure it out and initiate this potent immune response to the tumor.

Dale Shepard, MD, PhD: Do you have preliminary data on tolerability of these vaccines?

Natalie Silver, MD, MS: We have done all the preliminary toxicity studies in mice, and actually, we have done the preliminary toxicity studies in dogs with naturally occurring GBM and osteosarcoma. Then, I'm actually running a trial at the University of Florida with the College of Veterinary Medicine in cats with oral cancer.

We have treated five cats now. These are pets. These are not lab cats or anything like that. They are people's pets, that have cancer. We have done dose escalation and we've been investigating the safety. Primarily, the canine data from my partner contributed to FDA approval, as well as some of the feline data. We were a little bit after that. We have definitely investigated all of these. We think that this is a safe vaccine.

Yes, of course, some of the dogs had fevers and there is a profound immune response, because a lot of the efficacy is actually driven by interferon alpha, which is a very potent interferon that can mimic being really sick. We anticipate with human, that we are going to encounter some side effects, but in general, it is very safe, as far as we know.

We are excited that in the end of March, we are actually going to be treating our first human at the University of Florida with brain cancer. We already have enrolled the patient and made the vaccine. We're waiting for the patient to finish radiation. Then, we are going to be doing the first in-human administration. My hope is, once that is shown to be safe, hopefully in at least maybe a couple patients, we will then plan to apply for FDA amendment to add head and neck as a site.

I have a lot of preliminary data in mice, demonstrating efficacy, as well as in our feline trial, demonstrating safety. In head and neck, I think we are going to be using this vaccine in conjunction with checkpoints, PD-1. I imagine that we will initiate the trial in patients that have failed first-line PD-1 in the recurrent metastatic setting. Then, the trial that we are thinking about would be administrating our vaccine and then restarting PD-L1, because the data that I have in mice demonstrates significantly a synergistic effect with checkpoints.

As you know, with these types of things, it's usually not one thing that does the job. I think, obviously, this is a complicated disease to treat. I think that the checkpoint, along with the increased antigen expression and immune cell activation, is going to be the best way to decrease the tumors in these recurrent patients that have really difficult-to-treat cancers.

Dale Shepard, MD, PhD: When we think from a logistics standpoint, patient shows up, they have a tumor, we talked a little bit about the timeframe involved. You have to get the mRNA, you have to get the nanoparticle, you have to administer. What kind of timeframe are you looking at?

Natalie Silver, MD, MS: It takes about a week to make it.

Dale Shepard, MD, PhD: That's not bad.

Natalie Silver, MD, MS: Yeah. Right now, we're making it in Florida. Eventually, I'd like to make it here. I've talked with Tim Chan, who's my boss here over at the Lerner Research Institute, about the GMP facilities that they're working in. That's all in the pipeline. Eventually, we could probably make it here, but right now... It's a huge process, obviously, to get another site approved.

We would make it in Florida and then they would ship it here, which my partner, Dr. Sayour, who is the pediatric neuro-oncologist, he has already gone through the process of shipping, because his trial that he's initiating is a multi-site trial. For a lot of cancers that we work on, this can't be just done in one center. We need to get the patients. It is stable to ship. There is quality control and things like that. Logistically, it takes about a week to make. Then, shipping, as far as we know and have tested, it is safe. Then, we could administer.

Dale Shepard, MD, PhD: It looks like lots of exciting things will be coming up in the vaccine area.

Natalie Silver, MD, MS: Yeah.

Dale Shepard, MD, PhD: Maybe we could just touch really briefly on something that you mentioned, and that was the oral microbiome. You hear a lot about gut microbiome and you don't hear as much about oral microbiome. Tell me a little bit about what you're doing in that area.

Natalie Silver, MD, MS: Yeah. I'm very interested in this area. We have some really exciting preliminary data and actually a paper that is currently under review in the Journal of Neoplasia in the cancer microbiome issue. What we have found is that the oral bacteria associated with tumor, versus adjacent normal, is very different. Now, this is not really a new finding, but what we did find in our recent study in collaboration with MD Anderson, which is where I train and have some mentors and partners that are still working there, we looked at patient specimens, patient samples, and demonstrated that there was a preponderance of Fusobacterium, which is known to be involved in colon cancer and other cancers. It's called a pathogenic bacteria, pathobiont, which is a pathogenic bacteria in the mouth.

We demonstrated that Fusobacterium is significantly associated with the tumor, versus the normal tissue. We were able to show a correlation between that and PD-L1 expression. What we did was we, then, did some work in the lab and looked at some of our head and neck cell lines. We infected the cell lines with Fusobacterium and other strains of bacteria. It demonstrated that we can actually induce PD-L1 mRNA expression, as well as protein expression.

Our hypothesis is that there's certain bacteria in the oral cavity that can really promote PD-L1 expression, among other types of immunosuppressive checkpoints, and contribute to potential tumor cell evasion or tumor progression. We have a lot of ongoing work now, also, with Mohammed Dwidar in the Microbial Culturing Core here at Cleveland Clinic.

There's a lot of really cool work going on in the Lerner Research Institute in the metabolic section, where there's so many resources for investigators. They offer a lot of sequencing for bacteria and they have a germ-free facility, which is really great for preclinical investigations in microbiome.

We're going full force ahead with all that stuff, too. We're relating it to our vaccine work in that, I think, the focus is going to be on the tumor immune microenvironment. I think that, whether you're looking at a vaccine effect on a tumor or you're looking at bacteria effect on a tumor, it's still the same fundamental question. What is this doing to the tumor? Is it causing increased infiltration of protumorigenic immunosuppressive immune cells? Or is this causing infiltration of anti-tumor immune cells?

We're remaining focused on the tumor immune microenvironment and strategies to look at that, but looking, also, at bacteria and how that plays a role. I think, like you said, the tumor microbiome is very different, I think, than how the gut interplays with checkpoints. The gut, I think that it's been established or there's a lot of incredible research out of MD Anderson and other great institutions, demonstrating that specific gut profile can dictate how you respond to checkpoints, and if you have antibiotics, it could really effect that.

I think that the story is very different in oral cavity. I think that bacteria within a tumor, they don't play by the same rules as the gut bacteria. I think it's a very different question. I think that the oral bacteria plays more of a pathogenic role in that tumor's existence and resistance to treatment. I think there's a lot of cool questions and interesting new techniques that can be used to look at this question.

Dale Shepard, MD, PhD: You're doing some fascinating work. Best of luck, as it moves forward. We really appreciate the insights.

Natalie Silver, MD, MS: Thank you so much for having me. I really enjoyed it. Thank you.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

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