The Latest on Oral Cancer Clinical Trials
As Director of Head and Neck Cancer Research at Cleveland Clinic, Natalie Silver, MD, MS, FACS shares some of the exciting and innovative trials she's leading to bring about a cure to head and neck cancer. Dr. Silver's work has received a grant from VeloSano - our premier cancer research fundraising initiative - listen and learn more about how you can get involved.
The Latest on Oral Cancer Clinical Trials
Paul Bryson: Welcome to Head and Neck Innovations, a Cleveland Clinic podcast for medical professionals, exploring the latest innovations, discoveries, and surgical advances in Otolaryngology - Head and Neck Surgery.
Thanks for joining us for another episode of Head and Neck Innovations. I'm your host, Paul Bryson, Director of the Cleveland Clinic Voice Center in our Head and Neck Institute. You can follow me on Twitter @PaulCBryson, and you can get the latest updates from our institute by following @CleClinicHNI, that's @CleClinicHNI.
Today, I'm excited to be joined by Dr. Natalie Silver, our Director of Head and Neck Cancer Research here at Cleveland Clinic. You can follow Dr. Silver on Twitter @NatalieSilverMD. Dr. Silver, welcome to Head and Neck Innovations.
Natalie Silver: Thank you, Dr. Bryson. It's very nice to be here.
Paul Bryson: It's so nice to have you join the team and to be your colleague. Let's start by having you share some of your background for our listeners, where you're from, where you trained, and how you've come to Cleveland Clinic.
Natalie Silver: Sure. I did my medical school training at Georgetown University and that's also where I got my graduate degree in tumor biology, which started my interest in translational research and basic science. I went to medical school at Georgetown University, as well, and then I did my residency at the University of Kentucky in otolaryngology. And then I did a two-year fellowship at MD Anderson. One year was a clinical-based fellowship where I focused on ablative cancer surgery and the other year was a research-based fellowship where I spent the whole year in the lab with my mentor, Dr. Jeffrey Myers, who's a leader in the field of head and neck cancer, basic science research. And then after that, I joined the University of Florida as an assistant professor where I was a 60% clinician-scientist. I developed a research program primarily focused in head and neck cancer vaccines, therapeutic cancer vaccines, and went on to receive some NIH grant funding. That's when I investigated opportunities at Cleveland Clinic and was recruited here to be the Director of the Head and Neck Cancer Research efforts.
Paul Bryson: Well, that's great. We're lucky to have you, we're lucky to have your expertise. For those listening, to be able to live and walk the walk as a cancer surgeon-scientist is not easy. I'm sure there's been challenges and hurdles along the way. If you could share, what ignited your interest to be this dual threat of scientific inquisitor and cancer surgeon? And then maybe share with us what's a week like for you, how do you organize your energies and commitments throughout the week as a surgeon-scientist?
Natalie Silver: So, that's a lot of good questions. You hit the nail in the head, where it is somewhat difficult to really excel in both and focus in both. But I originally knew I wanted to do something with research, basic research, when I was a master's student studying prostate cancer in a lab at Georgetown University and I just really liked it. I was there for four years as a technician, as well, so I had a lot of lab experience at the time. I knew that I wanted to be involved in cancer research and that's what made me want to continue that kind of research, but I also really did want human interaction. My mentor used to say, "You like people better than pipettes." And I think I do, probably, but sometimes I like pipettes a little bit more, it just depends on the day.
But I never ended up switching completely, I always loved that part of medical school where you're learning really more of the scientific component. I just always had a fondness for it and I had the background, because I had the master's degree and I had some advanced training, so when I went to fellowship, I think that was a really pivotal point, spending a year being totally engrossed in the lab, and probably one of the most cutting-edge labs for head and neck cancer research in the country, arguably.
Paul Bryson: For now.
Natalie Silver: For now, yeah. And so, after that experience, I had to decide, "What kind of job am I going to take? Am I going to be a clinician?" Again, I'm only ablative surgeon, so a lot of my colleagues have dual training in reconstruction, and so it's not the easiest for a completely ablative surgeon coming out, looking for jobs. I think sometimes, that research goes hand in hand with it, but that's what I prefer. I didn't really have any desire to learn the reconstructive part or to become an expert in it. That's really what propelled me forward, is just the love of understanding these things, and just having a knack for it and a comfort level with it, and so that set me off on searching for jobs that were for surgeon-scientists. And then as you become more ingrained in that scientific field and accelerate more, as you succeed, it just drives you more and more.
I started off with just not really knowing what I wanted to do at the University of Florida. I knew I wanted to do cancer research and I just tried a couple different things for a year, and then I met my mentor, Dr. Elias Sayour, who is a neuro-oncologist at the University of Florida, who really inspired me. I remember just listening to him give a grand rounds, and he's pioneering this RNA vaccine work that we're doing, and I remember just listening to him and just being so inspired. I just came up to him after his lecture and I was just like, "Let's do this, I'm on board. Let's try this in head and neck, let's cure head and neck cancer. Let's figure it out together," and he just welcomed me into the group and that was it. Getting grants and working together really just made it this incredibly enjoyable experience that makes me want to continue that and then also provide that for others who want to pursue this avenue, as well.
Paul Bryson: So, after the pivotal time that you spent in Florida and the success you had there with obtaining grant funding for your research, you've brought that expertise now to Cleveland Clinic and the Head and Neck Institute. Can you share with the listeners some of the major focuses and projects within the “Silver Lab” here at HNI?
Natalie Silver: Sure. So, the overlying focus is overcoming and learning about the tumor microenvironment, specifically, the immunosuppressive micro environment. One area of research is in the RNA therapeutic vaccines, so that's what my current funding is primarily on from the NIH, and that is to design and develop a RNA-based vaccine, mRNA-based vaccine, for head and neck cancer patients. A lot of the work is preclinical, so we use a lot of mouse models of oral cancer. We have many of them, we have models that replicate HPV-negative disease, we have HPV-positive disease. We're very comfortable with different sites in the head and neck, in terms of modeling. We also have thyroid models. And so, we're in the area, in the space, of trying to develop a therapeutic vaccine for all these. The way to do that is to run myriad of experiments, testing different formulations, different combinations, and then learning about the tumor immune microenvironments, so how can we manipulate the environment to overcome the disease? And so, that's a main focus of my lab.
We are actually now writing the human clinical trial for head and neck. So, my projection, hopefully, is that we will be in human clinical trials with this vaccine within a year. So, Dr. Geiger will be the clinical PI of the study, as she is a head and neck medical oncologist and expert, and I will be co-PI and primarily focused on the immune correlates and research questions. The goal of that, obviously, is to get it into a patient to cure patients with this. I'm very confident that this is going to happen. We have FDA IND for the use of this vaccine, this is through Florida, and we are planning to open the clinical trial here in partnership with Florida, so that's one of the main focuses.
Paul Bryson: I have not heard of head and neck cancer vaccine trials. Can you share, are there other trials like this at present in the United States?
Natalie Silver: Our group is running the first in-human clinical trial for intravenously delivered RNA nanoparticle vaccines in brain cancer in Florida. There are other trials that contain formulations of therapeutic mRNA vaccines in the United States, but this is the first in-human study of our patented formulation, which we have demonstrated has exceptional RNA payload delivery and immunogenicity and tumor efficacy. So, we have a lot of preclinical studies in mice, in multiple different cancers, as well as large animals, including canine and feline. So, we have an active clinical trial at the University of Florida Veterinary School, for which I am still the PI of, along with my veterinary colleague, Dr. Carlos Souza, and this is a clinical trial on cats that are pets, so they're pet cats that get oral cancer, so this is a spontaneously occurring cancer.
We've actually treated four cats since opening the study, which was about two years ago, we had to pause for COVID-related issues, but we've recruited and treated four cats and three of them are still alive after more than one year, versus cats that don't get the treatment, their mean overall survival is months. So, we are getting great efficacy, as well as safety, the cats tolerated their vaccines very well with no adverse reactions, as far as we know. So, we have a lot of preclinical studies among different species demonstrating efficacy and safety of our vaccine. The second brain cancer patient was just treated with the vaccine recently in the University of Florida, and so we're excited to expand to other cancers, now that we're getting signals that this is safe. We'll have to wait a little bit longer until we are sure it's safe, but we are planning for the next studies.
Paul Bryson: That's so exciting, particularly for conditions that sometimes don't have a lot of great options or that have ablative or reconstructive options that are pretty tough, pretty difficult, and intense for the patients and their families. It's so cool to hear about technology like this to drive therapeutics. Here, I know at the Cleveland Clinic, we have the Center for Immunotherapy & Precision Immuno-Oncology, what is it like working with those individuals since you've been here? What's that experience and where does the future seem to lie with these therapeutics?
Natalie Silver: So, it's been amazing. The Chair of the Center is Tim Chan, and his group has been incredible. Working there has provided me a lot of opportunity to gain the well thought-out and expert bioinformatics pipelines that are available there, so we've been collaborating on different projects related to deciphering which immune cells are populating tumors, things like that. And then there's also the immune monitoring lab, which is excellent resource for clinical trials, and so as I develop this protocol with Dr. Geiger, we will be utilizing the resources more. But they have a world class immune monitoring capabilities, including the highest level of bioinformatic discovery, T-cell receptor sequencing, they're able to really do things that are incredible with understanding how the body's responding to treatments. The partnership with them is invaluable and opens up a lot of avenues for examining how our treatments are working in our patients, and so I'm very fortunate to be part of that group.
Paul Bryson: It's really exciting. I'm always amazed when I hear about these studies, when I hear about the deliverables, when I hear about this personalization of some of these therapeutics. I wanted to change gears slightly, I wanted to continue on the line of oral cavity cancer. I understand you have another interest in your lab with the microbiome. Could you share and describe, what does that mean? What is the microbiome, why should we care in the oral cavity, and what's going on?
Natalie Silver: Yeah, of course. So, you're right, the second major effort in our lab is related to the oral microbiome. The microbiome is the group of organisms, basically, that are not your human cells that live in your body, and that includes viruses and fungi and bacteria and all different organisms. We are focused, primarily, with discovering the role of bacteria in oral cancer. The role of bacteria's been well studied in certain cancers, such as colon cancer is the poster child of microbiome studies. In head and neck, there has been investigation in the area for quite some time, mainly focused in dental literature. There's a lot of things to learn about this field, though, so there's a big effort in my lab regarding the oral microbiome. We recently published a paper in Neoplasia, it's a cancer microbiome edition, in collaboration with folks at MD Anderson, my previous mentor, Dr. Myers and Jen Wargo, who's a world expert in immunotherapy as it relates to the microbiome, and another colorectal cancer expert, Christian Jobin.
Altogether, we collaborated in this paper demonstrating that specific bacteria are enriched in oral cancer versus the controls. We used cell lines and in vitro experiments to compare and we found that in the human samples, the tumors that had increased fusobacterium also had increased PD-L1 expression, which we know is important for immune evasion and also immunotherapy treatments, because that's the receptor that blocks. We treated our cells and culture with different strains of fusobacterium, to other bacteria, as well, and we were able to induce PD-L1 expression at the RNA level and at the protein level in our cells, and so that was the main findings of our recent publication. It opens up a lot of avenues to study exactly how this is working. We have clues, based on some of the other papers existing, that there are certain MIT can be involved in PD-L1 expression and we are looking at that further.
Paul Bryson: So, maybe some opportunities for different translational approaches or immune modulating type of therapies, based on what you're seeing in the cancer cell lines?
Natalie Silver: Exactly. It's difficult to say deplete fusobacterium in your mouth. Oral microbiome's different than gut microbiome, too, because, as you know, can rinse out your mouth, but things don't really stay there, whereas gut, I think, things can spend a little bit more time in transit, and so it's different, you have to think about it differently. But there are different substrates that can potentially be blocked for fusobacterium to bind or there are different targeting agents you can use for different bacteria. There's also probiotic formulations, so there's a lot of different potential opportunities for translation into clinic. I think we're at the level where we're still figuring out how best to intervene and what the bacteria means. Because I think that the certain bacteria might be needed to affect good response to therapy, but also might be contributing to the aggressiveness of cancer, and so I think that there's a lot to learn in the area. And then there's also a difference between the tumor bacteria and then the gut bacteria and how they interact, in terms of effects on the immune system.
Paul Bryson: It seems like it goes back to the tumor microenvironment explanation.
Natalie Silver: Exactly. And so, that's what we're focusing on in the lab, is we're looking at different ways to treat bacteria in a mouse or a cell line, and then we're looking at what is that doing to the tumor immune infiltration? So, right now, we're doing an experiment where we're precisely looking at that where we're ablating the bacteria in the mouse by broad spectrum antibiotics and looking at immune cell changes in the tumor micro environment. And then we have support to look at fusobacterium in more detail, and so we're going to be also using the similar models of oral cancer, mice models, where we give the bacteria to the mice and see where does the bacteria localize within the tumor? What's it doing? What is it doing to the cells? Is it affecting immune cell infiltration, and then is it ultimately affecting therapy?
Paul Bryson: Lots to learn. The complexity doesn't seem to end as our technology gets better, it seems like there's still perhaps more layers to unravel for targeting therapy.
Natalie Silver: Oh yeah, absolutely.
Paul Bryson: That's just in the cancer field.
Natalie Silver: Yeah. There's a lot. There's a lot at Cleveland Clinic, there's a great Microbial Culturing Core, so we've been using them a lot, led by Mohammed Dwidar. He's been a great partner and so fortunate to have him be able to grow different strains of bacteria for us to test, that's such a great and valuable resource. He can grow anything. He's got anaerobic chambers and anything you can ask for. We've been working with Naseer Sangwan in the bioinformatics microbial core, and so he's been helping us with 16S sequencing and other types of bacterial sequencing. These are projects that medical students from Case and Lerner College of Medicine have been working on with me.
So, we have several projects related to human tissue, not just cell lines and mice, but we're looking at the human tissues and we're trying to look at what different types of microbes are in larynx cancer, understudied cancers in terms of the microbiome. There's very few publications on larynx cancer, salivary gland, just other subsites other than oral cavity, and so I think there's an opportunity to just gain basic knowledge, which is the medical students here have been very talented and have been really doing a great job for me this summer and in the lab. I think that hopefully their projects will yield really interesting results that can lead to further investigations.
Paul Bryson: We're very fortunate here to have the Lerner College and to have the university program at Case Western, there's no shortage of some of our younger colleagues who are hungry and inquisitive. It makes for a great environment to do the village work of-
Natalie Silver: Oh, absolutely.
Paul Bryson: ... of running a major lab. I understand congratulations are in order, some of the research that you just talked about received a VeloSano Pilot Award to further support your initiatives. It's a great time to plug our Cancer Center. For our listeners, it's nationally recognized leader in cancer research. VeloSano is our premier cancer research fundraising initiative. We've raised about $30 million since 2014, with 100% of these funds directly supporting our 200+ cancer research projects and programs. As you look at these awards through the Cancer Center, what is the VeloSano Award offered your efforts here in the lab?
Natalie Silver: Oh, the VeloSano Award has been very wonderful and I'm very grateful to be a recipient and I feel honored to be part of that. It's really helping fuel some of the microbiome research and the research on fusobacterium, so some of the experiments that I mentioned are going to be supported by VeloSano. It's really letting us continue the work that was related to our recent publication and just take it to that next level. So, hopefully, results from those projects that are funded will lead to additional funding, and then, of course, publications and contribution to the scientific body of work. And then, hopefully, obviously, cures and translation, but the first step is to be able to run the experiments, have personnel, have the money to do the work. Definitely, this award is very helpful in those efforts.
Paul Bryson: For our listeners, thanks to all of you who have donated or rode in our Bike to Cure weekend. Even though this year's ride has already taken place, there is still time to get involved, there's an opportunity to look to donate next year, and for more information on how you can make a difference, visit Velosano.org. That's V-E-L-O-S-A-N-O.org.
Dr. Silver, I just wanted to thank you for your time. I really enjoy the opportunity to not only talk with you, but work with you. I love to see about new research and therapeutics coming forward, and it's been such a great addition to our Head and Neck Cancer Program and the Institute, just in general. As we wrap up, any final take-home messages or things that you want the listeners to know about the “Silver Lab”?
Natalie Silver: Well, thank you, Paul, for those kind words. I have really enjoyed working with you, as well, and your leadership in the Institute is really been excellent and your mentorship for the Cleveland Clinic Lerner students has been really great. I know that they're all getting to where they need to go and being encouraged by you, so thank you for all those efforts. The take-home message, I think, would be for a clinician who is interested in translational research or basic research, I think sometimes, at the Cleveland Clinic, because of the way things are set up where the Lerner building is over on the side and the clinical enterprise is running their thing, that there's a lot to offer here. I know people are really busy with their clinical practices, and I get overwhelmed with that, too, even though I'm not as clinical as my counterparts, even my 20% clinical occupies a lot more than that, as everyone knows.
When important cases come in or you need to call the patient who is trying to deal with their diagnosis and you're on the phone with them for an hour when you're supposed to be in the lab or on a research day, that's just how it goes sometimes as a clinician-scientist. But I think in order to be involved in scientific research, you don't necessarily have to be a clinical scientist. If there is something you're interested in over in Lerner, just reach out. People are very really wanting to collaborate, especially the PhD scientists that don't have the connections, as well. I would say if there's any interest, to reach out to maybe some colleagues that know a little bit more who's doing what over there, but there is a lot going on and I know that people are very willing and open to collaborate, so I would just encourage people to do that.
Paul Bryson: Yeah. I think the spirit of collaboration is one of the great things about Cleveland Clinic. I think no idea or bridge is not worth at least having a conversation about.
Natalie Silver: Absolutely.
Paul Bryson: To learn more about Cleveland Clinic's Head and Neck Cancer Program, please visit ClevelandClinic.org/headandneckcancer. That's ClevelandClinic.org/headandneckcancer. To speak with a specialist or submit a referral to our Head and Neck Institute, please call 216.444.8500. That's 216.444.8500. Dr. Silver, thanks for joining Head and Neck Innovations.
Natalie Silver: Thank you so much, Dr. Bryson.
Paul Bryson: Thanks for listening to Head and Neck Innovations. You can find additional podcast episodes on our website at clevelandclinic.org/podcasts, or you can subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. Don't forget, you can access realtime updates from Cleveland Clinic Head and Neck Institute experts on our consult QD website at consultqd.clevelandclinic.org/headandneck. Thank you for listening and join us again next time.