Episode 2: The role of microneedles in the delivery of cancer vaccines

John Price:

Welcome to coffee with Kindeva, a series of thought-provoking conversations about complex drug delivery. Today, we will be talking with Dr. John Vasilakos about the role of microneedles in the delivery of cancer vaccines. Hello, I’m your host John Price. And I’ve got John Vasilakos with me here today. He is an immunologist with training with over 25 years of experience in the pharmaceutical and drug delivery business spending much of his time working on the development of cancer, drugs, and adjuvants, as well as other chronic viral diseases. He is currently the business development manager for microneedle transdermal systems here at Kindeva drug delivery. So, John, what interested you about immunology that made you want to pursue it as a career?

John Vasilakos:

John, I was a as an undergraduate student, I took immunology and it was interesting, but to be honest with you, I really didn’t know. I didn’t know what type of a career one could have with it. And so after I finished undergrad, I, I got a master’s degree in microbiology and immunology simply because I was interested in it. And then I was fortunate enough to get a job at a pharmaceutical company, Eli Lilly, where I worked for almost three years, that’s when it really became clear to me what I wanted to do with my career, and then got a PhD at the University of Cincinnati. And then from there I’ve been in the pharmaceutical industry for greater than 25 years.

John Price:

So this ties in nicely with the next point from the article, which appears in On Drug Delivery we’ll have a link to it in the description for this episode in the article, you start by describing the prominence of checkpoint inhibitors. What are these checkpoint inhibitors and how do they work?

John Vasilakos:

Checkpoint inhibitors are either monoclonal antibodies or small molecules that block specific receptors that are on immune cells and the best way to describe checkpoint inhibitors and then checkpoint blockade in general is the sort of thinking of an analogy. So a car has an, a break in it and an accelerator in order to make the car go forward, you push on the accelerator and stop it you push on the brake. So the immune system is built in a similar manner. To make the immune system go, you activate it. And, and the immune system then turns off or slows down by applying a break. And this is a natural normal process that prevents an over-activation of the immune system, which can actually cause harm to us. So it’s normal to turn off the immune system. So what happens in cancer is tumor cells basically turn off the T-cell response or the immune response. They apply the break to the immune system all the time and turn it off. And what checkpoint blockade therapy does is it prevents the tumor cells from turning off the immune system. So in other words, it blocks the breaking ability of the tumor cells so that the immune system has the opportunity to become activated and to continue to be activated, to destroy the tumor.

John Price:

So when it comes to cancer, is there’s something that’s masking itself from, from our immune system normally.

John Vasilakos:

So yeah. Yes, definitely. So tumor in general tumors are there, first of all, their cells, they’re us. They’re not a virus, they’re not a bacteria. Our immune system doesn’t naturally recognize tumors the way that they recognize the way the immune system recognizes bacteria and viruses. So what tumors do is they have built in actually a number of immunosuppressive mechanisms that turn down the immune system. And one of those is checkpoint blockade, which we just talked about. And then there are other, there are other mechanisms as well. There are suppressor factors that are secreted by tumors that also the immune system from becoming activated and actually a whole slew of other factors that in general, cause the immune response to be very ineffective against tumors.

John Price:

So it’s like putting a wedge under your brake pedal in your car. You’re not applying the gas to the immune system. These inhibitors are saying, I’m going to take the break option away from you. So it allows your immune system to keep going normally is that an ap description.

John Vasilakos:

So yes, in part, so with, with cancer, the, the tumors themselves, the cancer environment itself is immune suppressive. All right. And checkpoint blockade therapies are a critical mechanism in order to, to turn off the immune system. So in, in general, your immune system becomes activated and it turns off. So it’s normal under normal circumstances checkpoint inhibitors play a healthy role and in an immune response, however, in the case of cancer, it’s, it turns into an unhealthy response because essentially what happens as soon as the immune system begins to respond against the cancer, the cancer vigorously defends itself by turning the immune system off. So in essence, what checkpoint blockade therapies do is they prevent the tumor from down-regulating the immune response, and therefore allowing the immune response to persist and destroy the tumor.

John Price:

There seems to be a lot of activity going on in the checkpoint inhibitor space. What are some of the upcoming trends in cancer, immune therapy

John Vasilakos:

Over the past five years, it’s become certainly apparent that it’s actually been, been apparent for even a longer period of time, but the big effort within the past five years really has been combination therapy, trying to identify the best combinations that work against cancer, because it’s pretty clear that under most circumstances single therapy is not effective. So checkpoint blockade therapy has become the cornerstone. And if you think about it, you have checkpoint blockade therapy, and then there’s a whole slew of other therapies, whether they’re, I mean, kinase inhibitors chemotherapeutics, anti-angiogenic, molecules, vaccines, et cetera, all of those are being evaluated in combination, really with checkpoint blockade therapies in the middle. So I would say in terms of up and coming trends, it’s trying to identify really which combinations will work the best. Certainly there’s a huge effort in we’ll call it personalized therapy where when an individual becomes diagnosed with particular type of cancer, then what their biomarkers are evaluated in the patient for the purpose of identifying in part the best therapies that will work. So we’re trying to look at at the tumor, basically the biological fingerprint of the tumor to help us predict which therapies will work best. So I think that’s another big trend that’s occurring and, you know, there’s certainly, we’re, we’re trying to identify new and improved checkpoint blockade therapies. There’s a lot of effort in vaccines, vaccine, adjuvants, et cetera.

John Price:

So with combination cancer therapies, the checkpoint inhibitors are going in trying to remove the breaks from working within our immune system. And then a second dose is given various cancer vaccines that try to accelerate or stimulate the immune system to actually go after and then attack this cancer. Is that what we’re trying to do with these combination therapies?

John Vasilakos:

Yeah, I think that’s a, that’s a re that’s definitely a reasonable example when you’re talking about vaccines, you know, and maybe it’s worth, at least mentioning here that checkpoint blockade therapy is very effective against certain types of cancers. And in general, what you could do is you could look at tumors and if they are populated with a large number of immune cells, for instance, and in particular, if they’re activated immune cells and we would refer to those as hot tumors, and that’s really where checkpoint blockade therapies in general have shown to be effective for cold tumors. And these are tumors that lack immune cells, here’s where checkpoint blockade therapy hasn’t been very effective. And this is really John is where we start thinking about, well, how can we increase the number of tumor specific T-cells and really logically this is where vaccination comes into play.

John Price:

So, so as you were just discussing you, you wrote about some tumors being hot, some cold, what, what makes some tumors hot and some cold? And what exactly is that referring to

John Vasilakos:

The, the simplest way to, to look at, to define hot and cold tumors is a hot tumor is a tumor that contains T-cells or immune cells and a cold tumor lacks immune cells. Now it’s not, it’s not that simplistic, but I think it’s probably the easiest way to explain it. And if you think about it, the way checkpoint blockade therapies work is the, the therapy is administered into the patient. And you can imagine that within these tumors, you have, you have T-cells, they have the ability to recognize and destroy the tumor, but they simply don’t, they’ve been shut off if you will. The brakes been applied to them, and this is where the checkpoint blockade therapies become effective. They, they remove that break and allow for those tumors to, to to be destroyed by the T-cells. So a hot tumor is a tumor that contains functional immune cells within the tumor in a cold tumor lacks an immune profile, a functional immune profile

John Price:

Does a tumor evolve from hot to cold or some tumors, always hot and some are always cold. Do they evolve throughout their time in the body? Are they hotter when they’re forming and then as they grow, they become colder or is it generally a static state of cold or hot, or is it a combination of both?

John Vasilakos:

Yeah, that’s a great question, John. And actually pretty difficult one to answer, but in general as tumors, as a tumor enlarges, it becomes more immunosuppressive. I mean, just it’s a general generalization. It’s definitely not always, always the case, but if you, if you had to put a timeline on cold to hot on tumors, the longer the tumor persists in the larger that it becomes the colder, it becomes within the host. But in general, I would say that’s probably, I’ll say it’s a difficult to answer question.

John Price:

So does this help explain the importance of delivery of the cancer vaccines early in a patient’s diagnosis?

John Vasilakos:

So we’ve known, we’ve actually known for some time that cancer therapy, whether it’s immunotherapy or not, is more effective when tumor burden is low, so larger, the larger the tumor, the less likely the traditional therapeutics become effective. So in general, I would say that that’s the case. That’s always been the case.

John Price:

Generally. It sounds like you’re a little more encouraged now than you were 10 years ago about the state of the science here is, is that accurate.

John Vasilakos:

Definitely. I, I mean, I think so if you think about cancer therapy for decades, I mean, we, we were hoping to put, to bring therapeutics to the table that would allow for patients just to live an additional six months, really what happened in 20, between 20 2005 and 2010 say that timeframe there was there’s this explosion in immunotherapy and really a great understanding in checkpoint blockade and its role. So we’ve known for some time that we’re able to induce immune responses to cancer. We’ve been able to do that through vaccination. The problem is, is you’d get a response and then the response will be turned off. So what happened, you know, around 2010, we started to have checkpoint blockade therapies, which were being developed and evaluated in the clinic. And we saw what we saw, which is really encouraging, is not only was the tumor and the cancer either reduced or held under control, but that the patient was living for a long period of time. So essentially these therapies became what we call they allowed for durable responses. People were living longer.

John Price:

Talk to me about the potential advantage of delivering a vaccine intradermally

John Vasilakos:

Sure this kin is, is a natural, it’s an immune working. If you will. It’s loaded with immune cells, particularly a certain type of immune cell called a dendritic cell or dendritic cells, just different types. And the, these dendritic cells, their function is to up relevant antigens or a substance that you want to induce an immune response to. They then take that and deliver it to T cells in the lymph nodes. And then you get this activation of an immune response. And so I think probably a good way to think of it is it’s about plumbing, basic plumbing. If, if a vaccine is administered into the muscle muscles, not a normal location where an immune response occurs there, isn’t this, this natural migration of immune cells that go into the lymph nodes, where you initiate an immune response, the skin, however, is set up. It’s basically built for an antigen is when bacteria, when viruses, et cetera, get into that site. They’re picked up by initial presenting cells, dendritic cells, they then migrate into the draining lymph nodes, and then you induce an immune response. So it’s a more natural way to actually induce the immune response.

John Price:

You’ve also written that there are other organs other than the skin, like the spleen or other lymph nodes. Why are we delivering to the skin versus directly into the spleen? Are these lymph nodes? Is it just easier?

John Vasilakos:

Sure. I mean, I think that’s probably the best answer. You know, if you think about to deliver to the spleen, the lymph node would require specialty techniques and likely an interventional radiologist in order to do it. So you need you’ll need a skilled individual and you’ll need specialized equipment to do that. All right. And I would say the lymph nodes, I can understand administration and lymph nodes, but the one thing I would say about the spleen, the spleen is definitely an immune organ. It’s a B-cell rich organ. And if I had a preference, I go into, into the draining lymph node, into the tumor draining lymph node for vaccination rather than into the spleen. But in either case, it just, it makes more sense. It’s easier to actually go into the skin.

John Price:

What are some of the traditional challenges to intradermal delivery

John Vasilakos:

Today.. .to do an intradermal injection, it does require some training and some skill, certainly, and often even a skilled individuals. It’s estimated that about a third of the time. They’re not completely accurate in delivering into the dermis. So what happens is they’ll go inject some of it subcutaneously some of the solutions subcutaneously. I think another problem is also volume. So the typical techniques that are used today are, or tools that are used today, allow for administration of about 50 to a hundred microliters for your typical vaccine solutions. They’re generally a half a mil to a mil and solution

John Price:

Potential solution for consistent intradermal delivery. Can you describe what this device is? And a little bit of how it works?

John Vasilakos:

So number of companies Kindeva included are trying to produce devices that will allow for accurate and consistent delivery of antigens or solutions into the, into the skin. And Kindeva has developed. We have two devices one’s called our solid microneedle or sMTS. And the other is a hollow microneedle hMTS device that allows for the administration of antigens into the skin. Now the solid device essentially is a aqueous system where the vaccine formulation is dried onto the microneedle. And then that microneedle is inserted into the skin. And when it gets delivery of the antigen in the skin and the hollow solution, that’s administered into the skin, just like you would administer a solution with a, with a standard needle and syringe.

John Price:

I am trying to picture of the device. So it’s delivering a fluid similar to a traditional needle and syringe, but at a more consistent penetration depth, are there other advantages to these hollow microneedle systems or hMTS beyond consistent penetration levels? It sounds like the cancer vaccines are often delivered in larger volumes. Is there something that the can debit hMTS device does differently to traditional delivery?

John Vasilakos:

Some of the key advantages of the of Kindeva this hollow microneedle device is that it delivers solutions that are half a mill up to two mills. And this is really a big differentiator in comparison to other devices that are out there. Because most of the vaccines, as we had mentioned, they’re typically in the half a mil to one mil range. So there’s this in that volume, other devices simply don’t allow for that large volume delivery into the skin. And I think that another key aspect is the consistent delivery within the dermis of the skin. So the dermis is a layer of the skin that contains a large number of relevant immune cells, especially dendritic cells. So you’re actually, you are directly putting your vaccine in a location that has the appropriate immune cells to pick up your vaccine and take it to the T-cells in order to induce an immune response.

John Price:

That’s really interesting. What kind of clinical testing has happened with both the hMTS and sMTS devices? Are they currently being used in any active trials?

John Vasilakos:

Actually, the solid microneedle device is currently in phase three, clinical testing Kindeva is working with Radius Health radius health is the sponsor of the program. The device is designed to deliver a peptide for osteoporosis. And like I said, that’s in currently in phase three and the hollow microneedles are, have been evaluated in cancer patients. There are two organizations, both the Mayo Clinic and Sensei Biotherapeutics that are using Kindeva this hollow microneedle device in order to administer their vaccines. Mayo clinic is administering a dendritic cell vaccine for glioblastoma patients. And as well as ovarian cancer patients and Sensei Biotherapeutics has administered into head neck cancer patients, a vaccine, which consists of essentially recombinant virus that encodes the relevant cancer antigens.

John Price:

I’ve read some articles about microneedles that dissolve in the skin. Is this what we’re talking about here, where the needle is actually just go away after the drug is delivered? Or is this something different?

John Vasilakos:

Yeah, great question. This is something different. These devices are designed to administer the drug and then the needles after administration, they are removed and discarded. So this is not a dissolvable microneedle type device. The one thing to note is, so even when you think about the manufacturer of vaccines for the dissolvable microneedle technology, what one would need to do is they would need to formulate the vaccine and then incorporate it into the microneedles during the manufacturing process, the, how a microneedle device, all right. One of the advantages, I think with a hollow microneedle device over a dissolvable is that you can, one could manufacture the vaccine at an independent site, say for instance, a bio-pharmaceutical company can manufacturer its vaccine, whereas Kindeva will manufacture the device. So when it comes time to administer it to the patient, then the vaccine formulation is floated into the, into a cartridge that fits within the injector of the hollow microneedle. And then it is applied to the patient’s body and administered into the skin

John Price:

What makes hollow microneedles well-suited to the delivery of cancer vaccines, specifically

John Vasilakos:

A couple of things. Do I think, first of all, cancer vaccines, we’re really trying to induce a strong T cell response in general. And so what we want to do is we want to increase the probability of getting the best response that we can. It seems like a pretty good idea to administer into an area of the body that can increase the probability for giving you the best response. So the skin does make sense for that. The other reason is that the microneedles the tips of the microneedles are 80 microns in diameter. And the part that’s important here is one can administer cells that can administer viral particles as well as standard protein, adjuvanted vaccines. And I think a lot of the cancer vaccines that are being developed today are cellular in nature and then common and, and viruses in nature. So the technology fits.

John Price:

I really appreciate your time today and for enlightening us about cancer, vaccines, checkpoint inhibitors, and combination therapies. I look forward to hearing from you again as the current trials progress. Thank you for listening to coffee with Kindeva, a series of thought-provoking conversations about complex and drug delivery. Join us next time. As we talked with Ben Myatt about novel investigations of the next generation of pMDI propellants.