Mohammad Khan

Bret Kugelmass
We are here today with Dr. Mohammed Khan, who is a physician-scientist, and an associate professor of radiation oncology at the Winship Cancer Institute at Emory University. Dr. Khan, thank you so much for taking the time.

Mohammad Khan
Thank you for the opportunity.

Bret Kugelmass
We're super excited to learn about your work, especially as it relates to COVID. But first, could you just give us an introduction as to your past, your history, stuff you've worked on before?

Mohammad Khan
Sure. So I'm a nuclear engineer by background. I did my Ph.D. in nuclear engineering at the University of Tennessee, Knoxville where my focus was on health physics and medical physics. And, more specifically, my research involves image fusion and image registration to help improve treatments for glioblastoma patients undergoing trials. I got interested in clinical research and taking care of patients at the bedside. Therefore, I went on to receive my MD from the University of Tennessee in Memphis. And that original call of duty provided me the best field to have patient access, patient care, and bring innovation to the patient bedside. And then, after I finished my radiation oncology residency training at Cleveland Clinic, I joined Emory University in 2011. And I've been here since then. I'm currently an associate professor who focuses on translational research and bringing innovation and new ideas to patient’s bedside to help improve their outcomes and help them live longer and have a better quality of life using radiation principles.

Bret Kugelmass
So first you got a Ph.D. in nuclear engineering, and then you became a doctor as well, you got an MD after that?

Mohammad Khan
Yes.

Bret Kugelmass
And just so I totally understand, in addition, do you have an active practice where you treat real patients in addition to also being a professor?

Mohammad Khan
That is correct. So I treat patients with radiation every day now, at least two and a half days a week I do that, and actually, at our basic sciences lab, we radiate mice and do experiments with radiation, and then we do clinical trials off of that and take those clinical trials to patient beds. I help further advanced their treatments and help bring new ideas and new treatments for them in the future.

Bret Kugelmass
So you're a scientist, a professor, and a doctor.

Mohammad Khan
Yes. I wear a lot of hats. I'm considered a clinical scientist. A clinical scientist is someone who does clinical care takes care of patients using the standard of care treatments, standard care approval processes. But then also, I'm a scientist where I bring new things, new ideas, new indications that we learned in mice and experiments in my lab. And then we do clinical trials to help bring them to reality and help advance and bring the new treatments to their bedside to the patient future.

Bret Kugelmass
Now, before we get into the use of radiation therapy for COVID, can you maybe just give us a little brief history of how radiation has been used for medical benefits overall and other spaces as well?

Mohammad Khan
Sure. So you know, radiation was discovered as early as 1895, by William Rankin.

Bret Kugelmass
You said 1895, as early as 1895?

Mohammad Khan
1895. I gave this lecture to my residents in 1895, they discovered x rays. And with those x rays, within a year after that, 1896, they started radiating skin for skin lesions. And they did really well. And shortly after in 1906, the American Dermatology Association thought it was the biggest breakthrough of its time to help treat skin cancer patients. 1906 was a big meeting in Washington that talked about this. And the minute it was discovered, I mean, radiation has been used for over 100 years to treat skin cancers. Even benign things back in the old days, they were using for pneumonia before the antibiotic era. They were using a for the skin to try to get rid of alopecia for patients. For lots of inflammatory diseases on the skin, it was used for acne for example. Matter of fact, there were orthovoltage tubes to help put patients’ feet and fit them for tubes, things like that. And I think the field was still learning, what are the appropriate uses. And we also learned what were the inappropriate uses of radiation. And so that was done, you know, probably 1920s until probably 1940s, and 50s. And probably after the 1950s, we figured out that radiation was a big therapy standard care for lots of cancer treatments.

Bret Kugelmass
So you know, oftentimes people think of radiation as a scary thing that causes cancer. But the more that I learn about it, the more I realize radiation has probably cured far more cancers than it is ever caused, is that right? And what orders of magnitude are we talking about here?

Mohammad Khan
A huge order of magnitude. I mean, you know, when we think about a 70-year-old versus a 60-year-old patient who's got cancer, and some of their cancer cure rates are around 95%, 98%. So for example, skin cancer patients, three and a half million patients out there, you know, the cure rates for those with skin cancer for early stage, you know, it's 95%, 98% with radiation. The likelihood of them developing secondary cancer from that is virtually nonexistent. I mean it's much, much less than 1%.

Bret Kugelmass
So we're talking about, we apply radiation to millions of people, we save millions of lives from cancer every year using radiation. And what are the, you mentioned inappropriate uses? What are some examples of when radiation has caused cancer?

Mohammad Khan
Yes, so I think, you know, in the 19- probably, you know, when radiation was discovered in the early 1900s, you know, 1900, 1910s, 1920s, they were starting to use it for what I would think was probably inappropriate uses. I think it was great to be able to image a patient's foot and to be able to look at the bones and look at the anatomy, you know, but the indicators were not to treat a disease process, the indication was just cosmetic to try to generate nice images. But then also for foot fitting, you know, to the shoes, and the sizes fit all of those back then didn't realize the late consequences 20, 30 years later, which can lead to small risks of secondary cancers. And then when they started treating children and younger patients, that was a bigger problem for the radiation policy field. And I think we learned from those mistakes that we should only use it for things that we can help patients with. For example, cancer, we know that cancer not treated in a patient is not going to do well, some may actually die, they may end up with problems, pain, bleeding, ulceration, all those things. So radiation makes perfect sense to help alleviate all these, and the risk of the small risk of 10, 20 years later, for the smartest cancers, it's not something that we would even think about, that the benefits outweigh the risk clearly in those settings.

Bret Kugelmass
And going back to that case, where I've even seen, you know, articles about this online, how they used to, you go to the shoe store, and you put your foot under the x-ray machine, and you map out your foot that way, how many people actually got foot cancer from that or some sort of cancer from that?

Mohammad Khan
It was if I remember, it was still very few, a very small percentage of patients. But I think the excitement was just hey, it was a new technology back then everyone wanted to see what their bones look like and I think that actually led to a lot of Superman comic books out there with the x-ray vision and being able to see. It was an excitement to be able to see inside your human body using x rays, and that never existed before.

Bret Kugelmass
And just so we do understand what the risk is, if you do use an inappropriate amount of radiation for these cosmetic reasons, where does it actually hurt you? Like what it causes, it causes bone cancer, blood cancer, skin cancer, if you're just shining it on your body just for any old reason? What is the negative way that it interacts with your body just so we fully understand the range of risks?

Mohammad Khan
So I think, you know, we think about several elements of radiation. When we think about the energy of the radiation, we think about the radiation dose that we're giving, the volume that we're treating, and then the age of the patient. I think will determine their risk for cancers, and what type of cancer that they will develop. If you're directly into the skin, very superficial, small area, the risk is probably nonexistent, or very minimal. But if you're treating like a total body patient, like the entire body, like for example, I treat patients with leukemia, and sometimes I have to treat patients that are very young because they have leukemia, that's a very deadly cancer, they will die from that if you don't treat them, you know, and I treat them. And I'm sure we understand there is a risk for secondary cancers many years down the line. But you know, for those patients that have a very short life expectancy without treatment, they're happy to trade-off that risk late, many years down the line for them to survive is more important than worrying about a 20, 30, 40 years later risk of having a second cancer.

Bret Kugelmass
Yeah, so let's talk about that leukemia. Is leukemia a blood cancer?

Mohammad Khan
Yes, leukemia is a blood cancer. That is correct.

Bret Kugelmass
And so what is the mechanism? Let's say you give someone a full-body dose of radiation treatment, what is the mechanism by which the x-ray or the radiation will negatively impact the leukemia, the blood cancer floating around throughout your circulatory system, more than it hurts the normal cells that you have throughout your body?

Mohammad Khan
Yes, so we know that cells that are carcinogenic, that are proliferating, that are growing faster, and which is what makes them cancer as opposed to other cells that are not proliferating at the same, you know, sort of rate, and that those cancer cells don't have very well defined repair mechanisms. So when you damage those cancer cells with radiation, that damage is not repaired very well. And these cells because they're proliferating, are much more sensitive to radiation induced damage, and they die off your normal cells that have very good repair capability. They've repaired, they rebuild, regenerate. And so they go on and they do well. And for leukemia cells, we do radiation. And there are two kinds of radiation we do. One is what's called myeloablative, working higher doses to directly destroy the leukemia cells to try to wipe them out in areas, that have leukemia cells high in some places like in the brain and the testes and things like this, a lot of the bone marrow spaces that even chemotherapy can't get to those areas. Without radiation, these patients would not do well. So therefore we offer radiation to get rid of all the leukemia. And then we also cause suppression of the immune system, so that they can accept someone else's stem cells to become part of their body and someone else's stem cells start to grow, they reproduce, the blood counts, the white blood cell, the platelets, all those things that they need to survive. So that's a mild later regimen. Now there's another regimen of radiation that we use, which is very low dose radiation, it's a lower dose, it's around two gray, a single fraction, that's called reduced-intensity radiation where all we're really trying to do is to modulate the patient's immune system, not necessarily cause a cytotoxic effect, but mostly immunomodulatory where we suppress your immune system so they can express and accept someone else's stem cells. And then those stem cells reconstitute in the patient and help lead to leukemia reverse the host effect where leukemia, a graft gets in and destroys the Leukemia. And you're and the body doesn't reject it, because you use low doses of radiation just to suppress your immune system, and we do that for elderly patients.

Bret Kugelmass
Yeah. How does that work? How does let's say two gray, two gray is what we're calling a low dose?

Mohammad Khan
Yes.

Bret Kugelmass
How does a two gray. And over a period of time, is that over a second or a minute? What period of time is that?

Mohammad Khan
Yeah. So it's a reduced dose rate, as well. So it's, it takes about, you know, about 15, 20 minutes to actually deliver the two gray, and it's an extended distance. So it's a very, very reduced dose rate, that we give that region as well.

Bret Kugelmass
And how does that suppress the immune system? What even is the immune system that, you know, you shoot lightwaves at it, and all of a sudden it, you know, it calms it down?

Mohammad Khan
Yeah. So the immune system is things like your immune cells. So this is what we're born with. So these are the lymphocytes. For example, the CDA T-cells are cells that are involved in sort of eradicating cancer, like getting your immune system to wipe out, a lot of the drug companies are developing drugs that can alter the CDA T-cells. There are also B cells that help produce antibodies. So these are sort of the cells. There are many, many cells and natural killer cells, these are all multiple, multiple cells of the whole immune system. And they all play different roles, and they all interact together to help, you know, destroy an infection, or help remove cancer, things like that. And radiation can help reduce or alter the function of many of these cells.

Bret Kugelmass
And maybe I'll just double click on that a little bit further, how does it actually alter the function of a cell? Does it? Does it make it uptake a chemical more selectively? Does it destroy a certain percentage of those cells? So then the other cells do something else in response? What is it actually doing when you send these x rays into a person? Like, how does it touch the cell?

Mohammad Khan
Sure. So I think, so x-rays, you know, are very different. They're not just one energy x rays. So depending on how you alter those x-rays, where you go to a very high dose of radiation, where if you're trying to blight tumors, that causes different physiological effects in the tumor. So for example, a high dose of radiation, which we call hypofractionation, can alter the cancer cells, where those cancer cells cause damage in the DNA. And that damage can lead to antigens being secreted on the surfaces and around the environment. So that's those tumor cells that are hiding from the immune system look different, they look altered, and your immune system can recognize them. And there are many, many things like it's like antenna receptors, where you've just taken that something that's hiding, you put an antenna receptor on it and your immune system can see it. And because you've caused antigens to be shared, you've changed the alteration of the surface. And by causing MHC class one expression, you've changed the whole environment around that. So basically, something that's hiding has now come out of that, I'll give you a great example that I give to my patients. For example, if you have something that's hiding in the bushes, and you want to be able to make it visible, and you want to make it come out of the bushes so that you can see it, you've targeted that bush and you add radiation to it, and that cancer doesn't like that bush, and he wants to come out and be seen by the immune system because he doesn't like what's happening. Then he comes out

Bret Kugelmass
It's like blasting a foghorn or something. It startles everyone, and people move from their hiding spots. And then the police can look around and say, ah, there's the bad guy.

Mohammad Khan
That's exactly right. And that's where the hypofractionation was trying to destroy that tumor. It makes it really damaging to that tumor, and he wants to come out of his hiding place now.

Bret Kugelmass
And what's the mechanism for the low doses.

Mohammad Khan
So the very low doses are where it changes the way that that tumor is active or not the tumor, but I would say the immune system is sort of functioning. So there's a nice paper that I can talk about, that came out from Gustave Roussy from France, Eric Deutsch's lab, where it looked at one of the immune cells that are involved in inflammation, for example, what they call the macrophages and looked at the production of those. So they looked at these, what they call the nerve and airway. So you have nerves and airways, and there are macrophages that sit around those airways, and they looked at what happened with low doses of radiation like one gray. And so these are cells that are supposed to be inflammatory. You know, these are the ones that cause inflammation. And the thought was what will low doses do to those cells? And can they change them from being inflammatory to anti-inflammatory? And the way to measure that is to look at things that these cells release to cause inflammation. So for example, when they become inflammatory, they're going to release IL-6, or interfering gamma, things like this. And you and the low doses, what they showed in a mouse model, were low doses actually reduced interfering gamma production, and reduce IL-6 production. And then there's another cytokine that's released, which is called IL-10. And the IL-10 was actually increased. And that's another mechanism by which they were able to conclude that low dose radiation converted those cells from inflammatory to anti-inflammatory. And the nice thing, they did some images where they took a mouse, and they took x-rays, where they injected these sort of what they call a Poly(I:C), or LPS, into the lungs to cause a RDS type mouse picture in the lungs of these mice. And when you give low doses, they show that the not only mechanisms wise where it those macrophages converted from an inflammatory to anti-inflammatory, but the nice images actually show where pneumonia in the lungs actually reduced and disappeared and got better with low dose radiation. So a good analogy could be like, for example, you have a, you know, we all have children, right? And your children are not behaving right. And they're acting up, you give a little consequence, say, hey, look if you don't behave, you're going to get a punishment. So these, these immune cells are the same thing, you know, they're inflammatory. And you're saying, hey, you're going to get a consequence. If you don't turn around and you don't behave and become anti-inflammatory. You better behave because low-dose radiation can alter them to saying, hey, you need to behave, you need to cut down the inflammation, you know, things like this. And there are mechanisms in biology that describe that.

Bret Kugelmass
So that okay, so this is a perfect segway into what's going on with the COVID. Because one of the problems and correct me if I'm wrong, but one of the problems that I understand is causing a lot of deaths for people who get COVID. It's not actually the COVID itself, but it's the body's overreaction to the COVID, that leads to inflammation that leads to pneumonia, and then that's what kills you. Is that right?

Mohammad Khan
That is correct.

Bret Kugelmass
And so what we're targeting with the radiation is not necessarily the COVID itself. But what we're targeting is the body's immune response to the COVID. That leads that oftentimes leads to death.

Mohammad Khan
That is correct.

Bret Kugelmass
And so now maybe, if we could rewind to history back a little bit, because there is an analogy, or there is a comparable, there was comparable work done in this space, specifically with pneumonia, and we know pneumonia is that response to COVID, that leads to death. We've had pneumonia for quite a while, you know, I know there's bacterial pneumonia and viral pneumonia, and antibiotics can treat bacterial pneumonia. But viral pneumonia has always been a little harder to treat. But they tried doing this way back when right with radiation.

Mohammad Khan
Yes, that is correct. So if you recall, we talked about radiation being discovered in 1896, or 1895. And, you know, in 1901, 1902 some of the early publications came out about how radiation can help skin cancers and things. And surely right after in 1905 the University of Pennsylvania, there was pneumonia, that was, and people were dying at a relatively high rate, there was not a lot of options for the pneumonia patients. And they then directed the radiation to the lungs, and they found pneumonia within I think six hours or within eight hours, these doctors would see these patients start to improve, their breathing would get better, their temperatures will drop, their white blood cells would start to get better. And clinically the patient would be improving. And within two days, or within three days after that, the x-rays also showed signs of improvement. And that work from 1905 to 1910s, 1920s just escalated there were more and more papers and more publication that came out in that area, I think there are reports for like 700 or 800 patients in that era, were treated successfully with radiation, a low dose of radiation to sort of help them get better from pneumonia.

Bret Kugelmass
And I understand, sometimes it's hard to tell, you know, in the medical space when you do something, if that thing actually created the positive effect, or if the person was just going to get better anyway. And that's why we have these controlled studies. But is the burden of proof a little bit lower if the result is so drastic, so quickly? Like you were talking about with eight hours? Is there a different metric that we use to measure that type of effect?

Mohammad Khan
Yeah, that's correct. So number one, I think that's one of the things about the pneumonia literature back then. They didn't do a randomized trial and partly because I think there's some actual discussion that said it was probably more likely unethical to even do a randomized trial on something that has such a big effect with something you have no other options for. It's kind of like who's going to do a randomized trial to prove that parachutes work. Right, you know, you can jump out of an airplane and have a quarter of patients that are not going to get a parachute. But, you know, as scientists we can say, hey, there's no randomized trial to show parachutes work. Right. But is it unethical to do that? So but regardless, I agree, I think the scrutiny and the proof of burden was not made available in the era of pre-antibiotic of the role of radiation for pneumonia, but it was used. And when antibodies came out, I don't think people have done this randomized trial of antibodies versus radiation for pneumonia. So that old data just sort of got put on the history shelves.

Bret Kugelmass
But that, that surprises me, because, you know, x-ray style machines, or radiation style machines are widely available, especially the diagnostic types. And we have billions of people on this planet, and not everyone has access to fancy hospitals. But you know, it seems to me, you know, a 15-minute blast of radiation to treat pneumonia, and there's probably, I don't know, millions of cases of pneumonia around the world, it seems to me like over the last, you know, 100 years, this would have been a fairly common practice to treat viral pneumonia specifically.

Mohammad Khan
Yes, that is correct. So I think a couple of things, I think, number one, probably because the antibiotics were easier to administer at the patient bedside, you know, patients, they're in the hospital, you give them antibiotics as opposed to transporting them down and radiating and things like that. Just number one, it was easier. And I would suspect, the antibiotics were probably cheaper to give as opposed to x-rays back in the day. And then I think, also, I think that's a field because remember, you got people that were using radiation for what it was meant to be, and balancing the risks versus benefits on behalf of the patients, I think we're championing and advancing the field in the right direction. But you also have other people with other means that were doing it for fun, they were doing x-rays for the foot, or they were doing it because they're going to have more customers to come into their shops, so they can get the right media attention or the right, you know, obviously, from a financial perspective, where they were using those x-rays to show a nice picture so that more customers would come in and buy their shoes. And that probably wasn't the right thing. And I think in those cases, it hurt the field of radiology because then those patients did develop skin burns, or they did develop some toxicity, or late cancers and things. And I think, and then also, I think that part of the negative attention overshadowed the positive attention to positive things of radiation. And therefore, I think in that era, when radiation could have been used for pneumonia, it fell apart and was never really championed and push forward because of the worries about the late risks of second cancers. And then also, if antibiotics were effective, and costs were needed, they didn't cost much. It made more sense to continue in that model in the era.

Bret Kugelmass
Yep. Just one quick point to clarify that though, the antibiotics don't work for viral pneumonia? Right?

Mohammad Khan
That is correct. They don't. And they've tried this for COVID-19, azithromycin did not work. Antibiotics do not work for viral pneumonia. That is correct.

Bret Kugelmass
And then what have people been doing for viral pneumonia over the last 60 years?

Mohammad Khan
You know, I think they've tried a lot of different things. They've tried a lot of antiretrovirals, things like this, or, and some of them have worked for different indications. You know, like for HIV, they use antiretrovirals all the time, and heart therapy works very well. You know, so there are lots of antiretrovirals that do work for various indications.

Bret Kugelmass
But that's been a fairly new thing. I mean, let's say like, even like, let's say, 40 years ago, when someone got viral pneumonia, the doctors tell them, hey, just tough it out. And hopefully, you'll get better or you're gonna die, essentially.

Mohammad Khan
I think they just tried off the shelf things to try to help whatever they could.

Bret Kugelmass
Yeah. Okay, so now let's fast forward to COVID. You know, it's March, everyone is freaking out, things are being shut down. We already know at this point, that it's a respiratory disease, and it goes after the lungs, and that it causes pneumonia, and that's a common cause of death. And that's when there were only you know, maybe, you know, 10,000 deaths in the country or, you know, maybe, you know, double that worldwide, or whatever it was, but people were freaking out. And we've got a whole discipline of people like yourself, who have these ideas, and they're like, okay, like this might work. What happened back in March, April, with respect to these ideas?

Mohammad Khan
Sure. So I agree. So I think to me, in February, I'm sitting there in my clinic, and all sudden your patients are afraid to come. As a doctor. I'm actually afraid to walk in and see my patients because I'm afraid of getting sick and carrying that virus home to my children and my wife. And but as a doctor, we do what's right, you know, we put our fears behind us and walk into the room and our patient needs to be treated. And it was a very grim moment. And I almost felt like I'm sitting, in what it might have felt like in 9/11 when we saw this in 9/11, where everything just, we were just in shock and awe, what is happening? And then you've got heroes, like the firefighters who say, look I’m ready to go out and save lives. We understand the building's collapsing on us. And thousands of lives are going to be lost in that building. And they ran in, while the fire was on and they ran and they got their gear on, they got their, you know, whatever they could have and saved as many people as they could. So similar to us, we have ideas, we can sit and brainstorm all these ideas forever while we lose lives in front of us. I could not see that. In my own field, people came out to criticize our ideas, let alone outside the radiation field, you know, pulmonologists, everyone else, like you're going to do what you know, but I could not see lives being lost and stand by and not be part of a solution as and actually become part of the problem. But some of those people actually became part of the problem by not wanting to do something. And partly because of their fear, they don't want to treat, they don't want to be

Bret Kugelmass
This drives me. This drives me crazy because we were in I mean, the whole world was in emergency mode. You know, when this you know last spring, and it seemed to me, just like as an average citizen, hey, let's try everything. I don't care how out there it is like, it doesn't have to work. People are dying anyway. So let's just throw every drug at the wall, every therapy at the wall. And yeah, some of them might seem silly or seem stupid. But if people are dying anyway, especially as they get to a certain progression in disease, like we already have precedents for allowing doctors to try random things on people who are about to die, right?

Mohammad Khan
Yeah, that's correct.

Bret Kugelmass
And yet there was still resistance?

Mohammad Khan
Oh, a huge amount of resistance against radiation. Oh, my God. People thought using radiation was the craziest idea ever. They thought people were nuts to even think about it. You know and partly because people forgot history, people didn't realize that radiation was used for pneumonia, and then they find reasons to sort of discount radiation because they said oh that's with bacterial pneumonia. This is viral. This is ARDS, this is inflammatory, this is very different, and they’re afraid and say you might actually make things worse and kill patients. So basically, they found a reason to not want to champion radiation, something that can help. And it really took different kinds of individuals, I would say, radiation heroes, to champion this in a time when there was plenty of doctors again saying they don't believe that radiation will help COVID-19 patients.

Bret Kugelmass
So tell me, what did you and your community, your group of heroes? What did you have to do to get things moving?

Mohammad Khan
So first is you know, you know, similarly, you know, it was a scientific leap of faith. You know, it's sort of like, okay, we understand the mouse models weren't there to really do that. The historical anecdotal evidence was there in the 1920s and 30s. But it hasn't been used recently. And we knew there is a huge bar and barrier to get people to be convinced. So basically, what I did was I built a team here at Emory. So I talked to my dear colleague, Dr. Hess, Clay Hess, and said, hey, let's, let's think about this. Let's brainstorm this because we can change the pandemic, we need therapy. We can't stand by. And if you remember, hydroxychloroquine came negative data, and there was nothing else at that point. Because that was the only thing we were hoping would have worked. And it wasn't. And there was a moment of silence. And

Bret Kugelmass
Yeah, we have to remind people, like we still don't really have, like, we got some stuff. But like, there's no like real good therapy, like the vaccine is different, the vaccine is about prevention. Therapy is about once you already have it, which millions of people do, or tens of millions of people have it, you know, this is about helping them and there is no real good option out there right now.

Mohammad Khan
That is correct. There is no really good option out there. So if you look at the number of patients that get diagnosed, the data suggests one out of five are going to end up in the hospital, they're going to need oxygen and support. If you look at February and March, if those patients in the ICU, the mortality rate to probably have died in the ICU was 50% to 80%. And these hospitals were getting flooded with deaths and our hospitals were shutting down and we're basically you know, we were shutting off the entire economy shutdown.

Bret Kugelmass
And okay, so 50 to 80% of people who get on the ventilator, essentially, is that the number of people who die

Mohammad Khan
That was the numbers back in February and March 50 to 80%, were going to die at the end of getting intubated.

Bret Kugelmass
And what about now? Yeah, what's the data now on that?

Mohammad Khan
Now, so the only therapy that has had some success in the intubated patient is steroids. And that has reduced the mortality down to about 30% mortality. So there's still a 30% chance that within 28 days, these patients are going to die, that's still a very high mortality rate. You know, I don't know of any cancers that have a 30% death rate within 20 days.

Bret Kugelmass
And that's crazy, and the way that steroids work is that in a similar function, it reduces the immune response.

Mohammad Khan
That is correct it’s anti-inflammatory, it reduces some of the cytokine storm and reduces some of the lymphocytes and their function. The exact mechanism they still don't know why steroid does this no one knows the exact mechanism. They just threw steroid out there as a guess and said it might work and let's try it.

Bret Kugelmass
And are there downsides to the steroid doses that they're using as well? Or is this a free pass that they tried?

Mohammad Khan
Yeah, no, there are downsides to steroids, it can cause reflux, it can cause long term use, can cause bone loss, it can cause ulcerations and the endocrine function of the patient, and it can worsen diabetes. And it can worsen the pre-existing if they have like a superimposed bacterial infection while they have a viral because somebody, if one patient actually has both they'll have viral-induced pneumonia, but they also develop a bacterial those bacterial infections can get uncontrolled on steroids too. So there are surely consequences of steroids.

Bret Kugelmass
And okay, so should tell me, where are the studies now? So you and your team have been pushing to study the use of radiation? And can you actually walk me through how much radiation? Is it compared to what they did historically? What do you think is the right dose of radiation? And what are the mechanics of how you give people a dose of radiation?

Mohammad Khan
Oh, perfect. So all good questions. So number one, you know, when we started reviewing the data in February or March and realized there is an argument, a scientific argument that, you know, we could put together with limited data sets, and both mouse data set preclinical data set, it wasn't ideal, it wasn't great, wasn't perfect. But still, it was a scientific leap of faith that it should work. So we put all that together went to IRB, got a protocol, you can imagine trying to get IRB approved was not easy to get all their own departmental team leadership to buy into it wasn't easy.

Bret Kugelmass
Are you saying like Review Board is that it?

Mohammad Khan
The Internal Review Board looks at the morals and ethics of a clinical trial, we're the first one in the world to be doing this. And there is no precedence with something like this.

Bret Kugelmass
And let me ask when hydroxychloroquine or some of these other drugs or any one of thousand drugs that they potentially use to try to work to develop a therapy for COVID. Were all of these done through clinical trials? Or were some of these used off label or off procedure just to see what might have worked?

Mohammad Khan
Many of these were used off the shelf. Hydroxychloroquine was used off the shelf, but the bar is not, it's easy for them to use off the shelf, any drug off the shelf, you wouldn't have as many issues getting approved as opposed to doing radiation. The scrutiny with radiation was it was a whole lot different element than any off the shelf drugs that don't have indications that you know, and it was easy to use drugs versus radiation.

Bret Kugelmass
Why is that? Is that a function of the review board’s procedures or function of how hard it is to access the equipment? Why is it so much easier to use drugs rather than radiation?

Mohammad Khan
Because it's just inherent bias. It's just an inherent biasing. It has to be a drug, it has to be an antiviral, it has to be this and that's why remdesivir was easy to get into trials. The hydroxychloroquine was easy to get into trials, many, many other things, they use lopinavir, ritonavir also came back negative that was also easy to get into trials there was no issues with getting those approved. You know, because it's an inherent bias, it has to be a drug. And it cannot be radiation that is just that's just the nature of what people believe.

Bret Kugelmass
And tell me but you were able to have some success. There are some trials right now going on that are studying the use of radiation therapy on COVID.

Mohammad Khan
That is correct. So the nice thing is, so we did the first trial in the world, we asked the IRB to allow us five patients, just for proof of principle. We're not asking to conquer the world. We're just taking small steps. And we can show that radiation is safe in those five patients and if they are happy with that they will give us the approval to do many more. All right, and we were set with the five patients. They were all elderly patients, the majority of them. They were all sick. They're to the point where they were actually crashing and many of them actually had worsening of brain function as well too because the clotting was probably impacting their high oxygen levels in the brain and they were getting demanded and their Glasgow Coma Scale's were dropping. And the nice thing is the first day when I walked into the patient, we brought them down on Friday evening after hours, radiate the patient. The next morning, walk into patient actually has a Zoom conference with her daughter. And that was amazing to see that.

Bret Kugelmass
This is someone who's gonna die. And a day later, they're chatting on video chat.

Mohammad Khan
That's exactly right. And that patient was amazing, and to me, that told me there's a signal the first patient that got on the trial. The second patient in the same night Friday we did two patients was, I can't give the exact date, but a well over 90-year-old lady. Similarly, the next day, we had a whole conversation to talk about her favorite sports team, the Atlanta Braves, and how she loves the Atlanta Braves. And we had a nice long conversation with her. And it was a completely different turnaround. And within 24 hours, the patients were coming off oxygen. Yeah. And these were patients that were not able to come on oxygen prior.

Bret Kugelmass
Yep. So any doctor looking at that situation would have said I predict this patient is going to die. And yet here's almost a miracle they are back to normal within 24 hours.

Mohammad Khan
Yes, that is correct, the reaction we got from our referring doctors here at Emory those same doctors that were skeptical about radiation was oh my god, look what just happened. So we need more science after that to know if it's going to potentially work and we just need to keep moving forward.

Bret Kugelmass
All right, so then what happens? So you get five patients? And then how do you get more now?

Mohammad Khan
Yeah, so with five patients, we have an 80% response rate at our mean time to get patients off of oxygen in one and a half days. So one and a half days, these patients coming off oxygen. If they didn't get radiation, they're on oxygen for a lot longer than that.

Bret Kugelmass
That's amazing. And, and then so okay, but how do we now increase the size of the set.

Mohammad Khan
So then I went back to the IRB and got more approval. So we give another five more patients to reproduce the signal. Because there's still skepticism, maybe we got lucky with the first one. Then we did five more patients and saw similar response rates. Our mean time to get the patient off of oxygen was three days. And what was happening is all of these 10 patients, when we looked at that data, after three days they came off oxygen, by day 12 they're getting out of the hospital, they're going home to their loved ones, their family members. And that was amazing. And then also what we found only one out of the 10 patients end up in the ICU. So 90% of the patients did not end up in the ICU. And then what we did was because we know the critique will be like oh, you know, you don't have any comparison, you have no comparative cohort. So we took 10 other patients that were age match, comorbidity match, and disease severity match and said hey, if this patient did not get radiation and what would have happened? And it turns out, those patients that would not have gotten radiation stayed longer in the hospital, it took almost 12 days before they came off oxygen. So 3 days versus 12 days difference in getting patients off oxygen. And it took them 20 days to go home.

Bret Kugelmass
Did any of that similar cohort end up dying?

Mohammad Khan
Yes. So with the 20 patients, it took 20 days to get those patients out of hospital versus 12 days. And then we had 40% of these patients ended up needing intubation versus only 10% with radiation. So basically, all three endpoints are, are in favor of radiation. So getting them off oxygen faster, getting out of the hospital a lot faster, and preventing them from getting intubated. And then and now if you look at the overall survival at 28 days, the overall survival was actually equivalent, it was still 90% for both of them and partly because those patients got intubated, they were able to stay longer, because they're intubated longer, right. So when you look at an endpoint of 20 days, you got people that are intubated, we don't know what they're going to do after intubation, whether they get extubated or not. But at 20 days we stop, and we look at the analysis, they both end up with equivalent survival but look at the quality of life differences. And look at these, you know, the ability to go home and all those. So all this sort of suggests that in favor of LDRT, and then to dig further into the data on LDRT

Bret Kugelmass
LDRT stands for low dose radiation therapy.

Mohammad Khan
That's correct low dose radiotherapy where we gave one and a half gray to the entire lung. And then we looked at to dig deeper you know, people want to see cytokines they want to see sort of inflammatory markers. So we looked at inflammatory markers, for example. So there are inflammatory markers like LDH, lactate dehydrogenase, or CRP. These are things that back then people said reduced CRP correlates to the survival of these patients and after radiation, we saw significant dips within 24 to 48 hours in CRP. And now we also showed LDH and many other inflammatory markers and cardiac markers and renal markers and lymphatic markers, multiple biomarkers also suggested the benefit of radiation. So we have multiple endpoints that suggest LDRT would work for these patients, low-dose radiation therapy, as opposed to you know, just get their standard of care therapies.

Bret Kugelmass
So you're able to test this out with 10 patients so far, or how many total?

Mohammad Khan
Yeah, so our 10 patient data. So the first five is already published in Cancer, our 10 patient data that compares 10 versus 10 has also been accepted in the International Journal of Radiation, Oncology, Biology, and Physics that has already been peer-reviewed and accepted. That will be coming out online probably in the next month or so.

Bret Kugelmass
And but to me, this seems like sorry to criticize you here. But it seems like it's going a little too slow. We've got hundreds of thousands of people dying. Yeah, and potentially, and that's just in the U.S. So potentially millions around the world are going to die if we can't bring out effective therapies faster. So hey, buddy, how come we're not moving faster on this?

Mohammad Khan
Because, you know, no one has paid for these trials. This is all voluntary efforts by my entire team working late evening hours after the clinics are shut down. We work after hours, we work on the weekend and work late. And we have a whole team of people, there's no funding for this. This is all voluntary.

Bret Kugelmass
And how come there aren't more people like you at every major hospital that has the appropriate equipment that has you know, uh, you know, someone with a radiation oncology background that has, you know, a friend who's a pulmonologist, or, or more people like you are around the country, around the world, trying similar studies. So instead of just having 10 people, we've got a collective 1000 or 10,000 people to look at.

Mohammad Khan
So that's a great question. So if you look at it from February or March when we started these trials, so when our first patient was treated on April 24, there was a lot of skepticism, there was no data, and nothing at all, till May, we faced the trials. And then in June or July, a lot more people paid attention to the data and said, hey, Dr. Kahn's team has shown five patient data and actually has 10 patient data now. Since then, more and more people have seen the data and said, hey, we need to do this. And slowly, slowly, the data is getting out there. And more and more people started to do the trial. So if you look at what happened in May, when we made the data available in the public domain, data from Iran came out in nine patients, though, actually five patients, I believe, initially, first five patients. They said they also see 80% response rates, and their patients are going home in very short time intervals where I think their average time to discharge was six days. So they were able to get the patient out within six days and an 80% response rate was using half a gray dose lower than what we used. And that came out. And when that data came out, then shortly after that data from Madrid came out where they looked at patient data in the hospital for a very long period of time. And they said look, they treated nine patients. And they found that their data also suggests is a benefit. And with that data coming out there, there are more and more trials, they're opening up, I know the VA Medical Center tried to open up a clinical trial of about 45 different hospitals in the U.S. There's an international society that is trying to run a trial in 26 different countries now because of that data. And Ohio State in the United States is also running the trial, looking at similar signals, and they have more bandwidth and more support now financially to help run a trial. So there are more and more leaders that are rising to the occasion and helping us advance the new therapy. Because we understand we need more therapies until the COVID pandemic comes into control.

Bret Kugelmass
Yeah, and, but something that still bugs me about this, like I understand when you're going through an official trial and official program, hey, you've got to, you've got to argue against your review board, you've got you know, your bosses, you've got to borrow the equipment, like there's a lot that can slow this down. But maybe, something that I still don't understand is, you know, we've got 10s of 1000s of doctors across the country, you know, I don't know, potentially a million doctors across the world that are treating patients coming into their hospital with this and like we said, like, you know, a lot of these, there's like a high percentage of people who are in bad shape that are going to need to be intubated. So we've got like, you know, let's say 100,000 doctors that could potentially be doing this off protocol or off label to try to save lives when they're looking at their options. And they're like, okay, I got steroids. I know the person's dying. Like, why aren't more people just trying it off protocol? And then we can go around and collect all of that data too?

Mohammad Khan
I think that's a great question. I think partly because as coalition and scientists, we understand the data is still small and limited. And we until we have randomized trials, and the government says, hey, we will pay for these large randomized trials, multiple institutions. We, you know, I don't recommend using this off-label at the moment. Now to add to the data, we're about to least another 20 patient data that we've created since the first patients, so we'll make that 20 patient data publicly available. That'll help people That'll help advance the therapy. And hopefully, Ohio State will finish their trial of I think 100 patients. So whenever they make that data available, as the signal gets stronger and stronger, and you have more confidence in the data, then I think people can start using it off label. But until then, I think we should only do clinical trials, or start focusing on using larger randomized trials and excel research by funding the research.

Bret Kugelmass
But why, I want to push back on you on this because like, when, when the situation is so dire, I understand, okay, we want to use trials for normal stuff. But like we are in emergency mode here, and like not everyone has access to great medical care, you know, across the world, I can only imagine what the situation is like in a country with limited medical resources, where the people aren't so rich like they don't have the hospital beds, the 12 days to like to treat people. To me, this sounds like something that you know, someone's about to be intubated, you give them a blast over 15 minutes. And then if they could be out the door, like, it just seems across the world, the situation is just so much more dire. And that it's worth trying more off protocol, work. If there's potential, like we're talking about saving hundreds of 1000s of lives.

Mohammad Khan
Now I understand I think you raise a good moral and ethical dilemma about the scientific rationale, the scientific data integrity, the data, and the robustness of the data versus the pandemic era. But I think the reality is, the data is still very minimal. You know, we only have three institutions that have reported data, Emory University is down to 10 patients, we will add 20 more patient data to that coming out probably the next couple of weeks. You know, Iran has their data. You know, Madrid has their data out there. But the data still weak. What if all of us got lucky, in the first ten patients it worked. Right? Or the first nine patients or however many we treated so far, it worked. But what happens with the next 100 patients or 200 patients, and we're trying to amplify that signal cause there are millions of patients across the world, and we may hurt patients because the data's not robust enough.

Bret Kugelmass
That was true with hydroxychloroquine and remdesivir. But those were used by 1000s, if not 100s of 1000s of doctors across the world off label just because we were desperate.

Mohammad Khan
I agree. No, that's a very good point. Honestly, I agree. I mean, I think, you know, hydroxychloroquine was used off label, and even when the data was negative, people still kept using it. People are still using it today. That's kind of unfortunate. But you know, the reality is, I think we have to be scientists, and we have to be very critical of our work. I think we have to be, you know, very careful. So I to me, I would still be skeptical, I would still want high robust data, just saying at some point, yeah, we can use off label, but I don't think we're there yet. But I think this is where there is an urgency and a sense of wanting to move this forward. I would encourage, you know, all agencies, the National Institute of Health, NCRP, any philanthropy, any funding agencies, whoever has the funds to want to move this forward, you know, we're not a drug company. It's not like, there's inherent money to be made in this, right. So direct comms are different with hydroxychloroquine, they have money to make, and they have a huge stock following the funds, so they can support their research and get that done. Remdesivir, similarily, pharmacy, pharmaceutical companies have funds. So they pay for all this research. With radiation oncology I don't see a lot of big radiation equipment manufacturers saying, hey, let's do this research. Let's accelerate this let’s fund it. Let's get it out there, what government agencies want to say, hey, we really care about the pandemic, and we want to support this research, and that'd be great.

Bret Kugelmass
But to me, though, that seems even more of a reason that people, that doctors should be trying this off protocol because there isn't this machine behind radiation like there is a machine behind these drugs promoting, it seems to me like the pragmatic reality is that if doctors don't, you know, take it up to themselves, that we're going to be desperately asking governments to help fund this for the next year, while countless of people suffer. I feel like, I understand you're cautious. You’re cautious as both a scientist and a doctor. And I'm not you know, I'm an entrepreneur. So I just want to make stuff happen. But I still feel like how dire the situation is not just in the US, but across the world. The bigger risk is waiting. Like even if we were to even if this even if you were correct, and we got the money to do the clinical trials. If we delayed that even one month, we're talking about potentially, you know, another 100,000 lives across the world that are lost just from waiting, you know, so it's like, I don't want to wait, I want to test everything on it. Throw it at the wall. I want to see if it works. You know control trials be damned.

Mohammad Khan
Yeah, no, I agree. I think this is where it really boils down to the individual sites across the world. You know how strongly they deal with 10 patient data files. And there are many, many cases in the medicine where people take off the shelf and try. But that's up to them at their level of whatever they feel in their comfort level, you know, I think that's fine with them if that's what they want to do. You know, there are case reports out there that are published in medicine. And we just take the individual cases for one or two patients. And we apply them, I'll give an example. Like, there was a young lady that I'm treating right now with an eccrine fibroadenoma. It's very rare, there's only a handful of cases in the entire world. And then that young girl has failed all therapies for her, you know, we know radiation worked for her brother, it worked for her dad. And she actually got things that are not working for her feet. And she has other options left other than having her foot amputated. And she's a young lady. And that's not acceptable for us. So we, you know, we only have a case for where we know, this works. And those that data set was weaker than the data for LDRT. But I'm using that case report to and ran it through our moral and ethical board, and we're doing an all protocol and actually radiating her so and she accepted the risks and benefits. But that's an individualized decision made on an individual level. At what point do you feel like evidence is enough to treat, there are many, many cases where things are done off the shelf, but that's more of an institution level. But from a global level, from a purely scientific level, from a more you know, the way things are done, you know, scientifically, we're not there yet that we can do it across all places, all institutions, until we have a randomized trial that compares LDRT versus standard care. Now, my phase three trial is open, I am running a randomized trial, right now, it might take six months or a year for me to get that out. And my research is becoming exhausted. And I don't know how long, or how quickly I'll be able to generate the data. But that phase three randomized trial is ongoing here at Emory. And we plan on treating about 150 patients. And right now we're, you know, we've got limited resources. So it's going very slow, I am reached out to several agencies to seed funding for that phase three trial, but I'm encouraging others to at least help champion that. And even other places to see if the theory works. And if it does, right, then we'd have the data much quicker, but then we can make it much more standard of care to say hey it works. Because it's like remdesivir, they actually did a phase three trial, got 1000s of patients on trial. Similar to the hydroxychloroquine, they did 1000 patients, they found it didn't work. But at least from that, we get to phase three randomized trial which has some benefit, not the benefit we hoped for but has some benefit. I would encourage people to say, hey, look, we may have a potential therapy, if you want to sort of make it fast and make a standard of care, then let's do it fast. Let's do a quick let's get these randomized trials up. Until then I have to be very skeptical, I have to be very cautious. The data is very limited. And any decisions at the individual level can be made at the individual level. But at a global level, I think we have to be careful and cautious about the data we currently have and assigned to you can only go with the data you have in the limited and you have to understand the COVID just you know, anecdotal it can be you know, luck that we all the three institutions are required. We just got lucky. Maybe who knows.

Bret Kugelmass
All right. Well, Dr. Mohammed Khan, thank you so much for your time today and for walking us through this. I you know, I think the work that you're doing is super important. And you know, I hope I can share it with the world. Thank you again for taking the time.

Mohammad Khan
I appreciate it thank you so much Bret for, you know, give me the opportunity to discuss some innovative research and some potential new areas we can grow into and help patients get better and prevent them from dying. Appreciate it. Thank you so much.