Cancer vaccines and mRNA; Irina Shkundina, Ph.D.

Hi, thanks for tuning in to episode #29 of The Doctor Podcast show. I'm Doctor Robert Seikart, your host today. Today we're going to be discussing a very important topic, and that topic is cancer. According to the latest CDC data, there are approximately 1.6 million new cases of cancer in the United States every year, which is unfortunate and even more unfortunate, about 600,000 people a year from cancer. In the past, we treated cancer with surgery, with chemotherapy, with radiation, and in recent years we're treating it with immunotherapy.

But there's a new development in the prevention and treatment of cancer, and that's cancer vaccines. So today we have a great guest, Doctor Irina Shkundina, and she is a senior research investigator at the University of Pennsylvania and at the Penn Institute for RNA Innovation. Doctor Shkundina also works with Doctor Drew Weissman, who's a world famous researcher. He won the Nobel Prize in Medicine just recently in 2023 for research and innovation. That led to the creation of the COVID, or coronavirus vaccine, which we heard about in the last few years during the pandemic.

Thanks very much for coming today, Arena. I appreciate your time taking the time to discuss this topic, which you're an expert in. Tell us about your education and background and how you got involved in in this type of research with cancer vaccinations. Thank you so much Robert for for this invitation and for this opportunity to speak here. So I come from from Russia where I received my undergraduate degree in Biochemistry from Russian State Medical University and I went into PhD program in the laboratory of Michael Terman Sam also in Russia and then some research in East Prions and there was a famous lab in East Prion Research.

After completing my PHDI worked in the lab of Constantine Severinov on bacteria antibiotics. And at some point I decided to move to the United States, where I actually started working in cancer in the laboratory of Alexander Mason and continued in the laboratory of Chris Eichen. And just recently, less than one year ago, I've joined the lab of doctor Drew Weisman to work on cancer vaccines. So we we kind of decided to unite our efforts. Drew is a great expert in immunology and I worked in cancer.

So he offered me to work in cancer vaccines. And this is a new direction in his lab because the majority of people in our lab work, work in vaccines for viruses, against viruses. So yeah, so, so this is a new direction and I'm kind of the first one to, you know, to start this cancer vaccine work. So we only in the beginning of our, you know, journey, but that's a great start because it's a great lab and, you know, great supervisor. Right. That's amazing that you're working with a Nobel Prize winner, Doctor Weissman.

What's it like working with somebody who's that brilliant and innovative and and has is known worldwide for all his innovations? What's that like? Yeah. So Drew Weissman is notably a great scientist, but there's a great person to work with. He's, he's very kind, very understanding and the great thing, he appreciates his people a lot So. And he allows people to, you know, to to speak their ideas and to implement their ideas. So that is when I come to Drew and tell him this idea. He always tells you that this is a good idea, you know, but then this is a good idea.

So it's a it's a good to hear. Even after afterwards he can say you know it's a good idea, but you need to be careful with this and that. And I'm going to start realizing probably not the not the great idea, but you know it's a good, I think that it's he's encouraging people to to think and to allowing them to, you know, to work independently. Right. I noticed you have a a large team in your lab that you work together. This takes, I assume, a lot of teamwork and a lot of effort with many people with various backgrounds in the field.

Is that right? Yeah, right. So you're currently working, I know on on cancer vaccines and I think there are other labs working on that as well. Tell us how cancer vaccines might work and and what is the mechanism for their effect. So the mechanism of cancer vaccine is that cancer vaccine brains immune system to recognize the cancer cell. So the cancer vaccines they are specific for the cancer antigens. So the tumor belongs to to the body so it composed of the cells of the human body. So in that in that sense immune system kind of sees it as its own and they're not always wants to you know attack that that's how the the tumor grows because the immune system allows it to grow.

Right. Normally the immune system is supposed to get of abnormal cells that don't belong there. But somehow tumor cells are are able to evade the immune system. It tricks the immune system into thinking the tumor or cancer is OK, and then the cancer grows, right? Yeah. So it develops like it immunosuppressive micro environment around the tumor and that allows cancer to grow. Right. So how would a cancer vaccine work to either prevent or I should actually say does do cancer vaccines prevent cancer or is it a way of treating cancer or is it both?

It's. Actually both. So the the majority of our current vaccines that are already now in clinical trials, they are therapeutic vaccines and they are either vaccines directed to a certain type of cancer like Melanoma, pancreatic cancer. There are also vaccines within the certain type of cancer companies now leading clinical trials to make patient specific vaccines for cancer. Patient specifics. So you're basically using the patient's antigens to create the vaccine. Yeah, right. So The thing is that the tumor has a lot of genetic instability and they're all mutations in a tumor.

So the how do we we need to to create a vaccine, we need to select this antigen in a tumor that is different from the whole body. So for several types of cancer, there has been some antigens found that can serve as an antigens for cancer vaccines. Also the tumors in every patients are different. So what works for one patient with Melanoma might not work for another patient with Melanoma. So what that, So what now like companies such as biotech and Madonna they are leading the clinical trials with so-called neo antigen vaccines.

When they take tumor from a patient, they sequence sequence the tumor, the DNA of the tumor they compared to the normal genome of the patient to the normal like blood cells for example. And also using computer algorithms that allow a lot of them to select because then when they just subtract, you know, they notice expressing the tumor to what is expressing in the normal cell. They get a lot of candidates but using some algorithms they select the most, one of the most candidates that that most probably work like the most important candidates.

And then from them in making mRNA for those kind of candidates and they can use like 5 to 10 proteins in the same vaccine. So create a vaccine with like 10 different antigens and then then immunize the patients with those vaccines. And then they do like you know 10 maybe injections. And then they see in the end how you know the patients is progressing what and they do it with the you know with disease which is you know like Melanoma third or fourth stage with the patients that are you know failing other therapies.

So, so basically you're taking antigen from the tumor, you're then are you reverse engineering that antigen, that protein from the tumor and making messenger RNA from that antigen and then the messenger RNA can create more antigen which you inject into the body. Is it? Is that what you're doing? Yeah. It's not what we are doing because for new antigen vaccines that are specific for particular patients that needs to be a big facility to do that. We're just a basic science lab. So we are why not doing new antigen vaccines, why not sequencing patients genomes.

We're just trying to find some antigens that we can work with. You know that will work for all patients with a particular cancer or with a group of patients with a particular cancer. That's what we are trying to find. One of the, you know, difficult tests for cancer vaccine is to find an antigen to immunize with And then there are other difficulties like how to find like immunosuppressive, you know, tumor environment which is also another big challenge in cancer vaccines. Right now you for the audience you mentioned mRNA or or messenger RNA, I think people are familiar with DNA by now.

But can you explain the difference between mRNA or messenger RNA and DNA? What what's the difference between those two things? So messenger RNA is like a middle, middle guy between DNA and protein that we all consist of proteins and we will have, we have the genes to encode these proteins. And then the messenger RNA is a middle, middle molecule that you know carries information from DNA to the proteins and this is the messenger RNA. So if we inject messenger RNA into the cells, the cells will create a protein from this messenger RNA.

Right. So you can create large amounts of protein and they can be customized and and be patient specific actually, right? Right. So the patient is less likely to have any side effects or adverse reactions since the protein is is patient specific. So the patient specific is is not always the case as I already mentioned NEO Antigens Lexine. We are not working on NEO Antigens Lexine because this is what big companies do. But so mRNA when it's injected into the body is degraded like in 36 hours. So the protein is translated as synthesized and it has the time to train immune system but then it's rapidly degraded so and that that kind of allows less you know toxic effects.

It doesn't integrate into or it does not integrate into the genome. So it allows brought into the express and then it's gone. So tell us about LNP or lipid nanoparticles. I believe this this is a way to get the messenger RNA into the body and to go to specific areas. Can you explain that the LNP or or lipid nanoparticles? Sure. So the lipid nanoparticle is like a vehicle to bring not only M RNA, it can also bring any therapeutics into the body. It's kind of protecting the molecule. If we inject M RNA, it can be degraded very rapidly because there are lots of RNA's and just RNA will be degraded and will not reach the target site.

I see. So believe it not a particle protects M RNA 1st and it also different LMPS have different composition and depending on their lipid composition and their charge that they can go into different parts of the body. Some of them go to the liver, some of them go to the spleen and some of them go to the lungs and people. Do you know a lot of work on creating the LMPS that target, you know, different size of the body? Right. So this is like an envelope, the LMP almost that that you stuff the messenger RNA into the lipid nanoparticle protects the messenger RNA so that it can get to the part of body that you're interested in and target a specific protein.

And then the the LMP kind of opens up and releases the messenger RNA when it gets to the address that it's supposed to go to. Is that how it works? Yeah, yeah. That's pretty fascinating. So you need different LM PS for different organs and and basically you have to customize that and you have to make sure they don't degrade on the way there, right. Hey, you mentioned an interesting thing and it's, it's been mentioned by scientists and and laypeople as well there, there's been some concern about the COVID vaccine specifically that maybe the messenger RNA is is producing DNA.

It's actually going backwards instead of producing protein, it may be creating some new DNA from some enzymes that exist in the body like it's called a reverse transcriptase enzyme. And and there's some concern by some people that you may actually be introducing foreign DNA into the human cells by some mechanism where the messenger RNA and codes for DNA. Is that Is that a reasonable thought or concern? Doesn't seem like a reasonable power because human cells do not express transcriptase and so they only reverse transcriptase can be in the human cell that come from from virus.

But since viruses, reverse transcriptases are known to be specific to viral RNAs, so it seems like this this concern is not, you know, very relevant. I think there were some in vitro studies where they found some DNA in hepatocytes or liver cells that seemed to be a product of the the messenger RNA. So I I don't know if that's been shown in vivo and a living person, but I I think there were some laboratory studies that may have shown that, but you don't think that's a reasonable. Infected with the virus or.

Yeah, I I forget exactly how they introduced the the messenger RNA into the in vitro hepatocytes or liver cells. But apparently they then found some DNA that had been transcribed from the messenger RNA. What if a person has some reverse transcriptase in their body from some other virus infection for example HIV and somehow the two get together and are extremely rare event is. Is it possible for that to occur? The other concern is some people are thinking, again, there's no definite proof of this, that the messenger RNA or the DNA product from the messenger RNA may introduce itself into germ cells, in other words, into sperm or or eggs in the ovary, and then be passed down into subsequent generations.

Is that science fiction or or is that a remote possibility? So since the lifetime of mRNA in the body is not too long, I don't think it's a you know the probability of the is is you know, significant probability of that to happen. I see, Sir. The MRI was in the body, you know, for years, and then I don't know, for months even, but the money is rapidly, pretty rapidly degraded. So, right, Right. Unless it's accidentally reverse transcribed into DNA, which again you mentioned is is unlikely to happen.

So yeah, we'll we'll see what happens, but it seems unlikely. Are there currently cancer vaccines in in clinical trials? Yeah, there are a lot of vaccines in clinical trials in companies such Moderna, and biotech has a lot of cancer vaccines and clinical trials, I see. Those are the companies that created the COVID vaccine. So they have experience in it. Are they? Is that a messenger RNA based cancer vaccine or or some other type of vaccine if you know. Yes, there are a lot of messenger RNA type of vaccines that that they are currently in clinical trials.

There are vaccines, Melanoma vaccine, pancreatic cancer, they're like solid tumors neo antigen vaccine. So it's like when they you know take away take away the solid solid tumor and sequence it and then develop vaccines specifically for a particular patient that do that for many solid tumors. So currently it's it's limited to certain types of cancers, but potentially if this works and we figure out how to do it, we we could target just about any cancer because every cancer has its own antigens or or proteins that could be targeted.

Is that right? Yeah, so, but potentially could work for every cancer. But there are challenges such as fighting the antigens specific antigens, so the vaccine will not target will only target cancer cells. Also there is such a problem as tumor heterogeneity because tumor may have several clones that different from each other and even when they take cells from the patient from premier one even they take from several you know parts of the tumor and create the vaccine. There may be another part of the tumor that will give you know new like for new cancer this can fight like some of the part of the tumor but another part of the tumor will outgrow will grow.

So this is another challenge and and and the third one is immunosuppressive microenvironment because the tumor is surrounded by this micro environment and then the cells of immune system just cannot get to the tumor mechanism preventing to getting cells to the tumor. Just a question, The tumor contains this antigen that that you're trying to attack. Why? Why isn't the body attacking the antigen on the tumor enough? Or why isn't the immune system attacking in? And is the purpose of the mRNA vaccine to just create huge amounts of this antigen or protein so that the immune system is is put on alert because there's so much of this protein floating around?

Is is that how this works?

So not, not not not exactly. The purpose of the vaccine is to kind of to reintroduce this antigen to the immune system and to train immune system to recognize this antigen. That's how it works. Why doesn't the immune system recognize it when it's on the tumor? Why do you have to send in the extra mRNA and and extra antigen? Is that known? Yeah. So there are some antigens that have low level of expression so so immune system doesn't see them or the presentation of the antigen. There are also the molecule that presented antigen to the immune system might be also some low expression of those molecules also tumor suppressive micro environment where they tumor cells express the molecules that interact with immune cells and they tell them OK we are you know we're not foreigners, we are OK and to attack them.

So and there there is a immunotherapy which is called immune checkpoint inhibitors where they block this interactions. Right. Some of my patients who have Melanoma are on those medications. They've been very effective for for many patients who've survived a long time and wouldn't have survived without them. So we're we're making good progress. What about using mRNA to as a vaccine for treatment for certain types of diseases, not cancer, for example malaria or tuberculosis or other types of infectious diseases that we don't have great treatments for.

Can the messenger RNA vaccines be used for that as well? Yeah, for sure. So there are vaccines for for HIV, for influenza and I think, yeah, malaria and tubercle, tuberculosis as well in clinical trials right now. Oh, so there are trials right now. That's that's great. And also our lab is also working on influenza and HIV vaccines, so we're hoping to get something at some point. That would be great because HIV for decades we still haven't been able to come up with the vaccine for it. So maybe this this new technology with messenger RNA may do the trick.

What about CRISPR has been in the news a lot, It's basically allows you to edit DNA. Do you use CRISPR also to edit the messenger RNA or or is that a different way that you're doing that? No, we're we're not using CRISPR to edit messenger RNA. So CRISPR it's on its own can be a therapeutic for let's say genetic diseases on the CRISPR, CRISPR system delivered to particular. I'm not an expert on that. So yeah, it's been recently approved for treating sickle cell disease and also thalassemia, which are two blood diseases, so.

Yeah. So for genetic, for for genetic diseases, different platforms, different CRISPR platforms are being collaborated for for that and also you know the companies work on that. But with RNA we're we're not doing anything with CRISPR. Without getting into proprietary things, how do you modify or edit messenger RNA if you're not using CRISPR? So the modifications. And Dr. Karika talked about it in her another lecture, so oh. OK, yeah, she was. She worked with Doctor Weissman on on the COVID vaccines, right?

Yeah. And so, so the modification, so mRNA consists of four nucleotides and one of the nucleotides such as uridine is substituted for soda uridine which have the same chemical composition which is an isomer of uridine. And when they found that this soda uridine when it gets incorporated into mRNA, it ensures our better mRNA stability and also this modified mRNA does not cause inflammation. So the body tolerates it. Yeah. Doesn't destroy right away, so. Oh, mRNA itself, yes. And doesn't and doesn't destroy it, yeah.

Well, that's that's a great discovery, definitely worth a a Nobel Prize in Medicine. When, when do you think we'll see the 1st cancer vaccine available for treatment after going through the clinical trials? Based on your knowledge and experience, when do you think that might happen? I know it's difficult to predict because they have to go through the trials. Yeah, right. So the vaccines for Melanoma for pancreatic cancer, they show in from 35 to 50% efficacy in clinical trials which is considered to be good.

So it might be I, I I don't know, but might be the new vaccine will be around soon, you know. Right. Hopefully another another question that when we use the word vaccine, we typically think of it as a way to prevent diseases. For example, measles vaccine or polio vaccine is given to prevent those infections. Do you think we're eventually going to have cancer vaccines to prevent certain cancers? For example, we know that people who smoke cigarettes are extremely high risk for developing lung cancer.

Will we get to a point where we have a lung cancer vaccine and anybody who's been smoking just gets that vaccine and it prevents lung cancer? Is that a possibility down the road? Yeah, it's certainly a possibility. And we're also working working on preventive vaccine vaccines in collaboration with other scientists and there are such cancers that hereditary, hereditary cancers, so patients with with BRCA mutations, they have predisposition, predisposition for breast cancer. Right. And so these patients are if they have like a family history of breast cancer, sometimes they they are dependent on their family history.

They have to just get their you know breast removed or over is taken out of the you know before they like when they reach 40 years which is very traumatic and in many senses. So it would be much better for these patients to to get a vaccine that will, you know, clear, clear out any first signs of cancer and. Are there any preventive mRNA cancer vaccines and clinical trials currently? Or is it just the treatment vaccines that are in trials?

Well, we are there are I think there are also some trials on the use of cytokines for for cancer. I'm not sure are they at the stage of the trials or it's a yeah, I think that there was a yeah there are like first stages of clinical trials in using of cycle cytokines which modulate immune system and they can stimulate immune system to affect cancer cells and that's what. Yeah, that would be. For as well. That would be an incredible accomplishment because many, many of my patients, for example, have various genetic diseases that predispose them to cancer.

So they're always being tested and they're always nervous and and worried about that. So that would be an incredible accomplishment. Well, I'd like to thank you very much for taking the time to join us today on the Doctor Podcast show. This was extremely informative and educational for me and I'm sure the audience as well. And I want to congratulate you and and Doctor Weissman for the incredible work you're doing which is helping millions and billions of of people around the planet. So thank you very much for coming today and say hello to Doctor Weissman for me as well.

Now thank you so much Robert, for, you know, writing me here. Also like to thank Doctor Drew Weissman for giving me such a chance to speak with you here. Been a pleasure. It's been a pleasure. Thank you very much and have a good evening. Bye, bye. You as well. Bye.

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