麻豆传媒

Topic: Cancer researchers are turning their talents to the fight against COVID, using strategies that have lead to breakthroughs in cancer therapies for years, such as precision medicine, immunotherapy, biomarkers, and more.

Who:

• - Director at The University of Kansas Cancer Center and Director at Kansas Masonic Research Institute (KMCRI)
• , Professor of Medicine, Director of Early-Phase Clinical Trials, Co-Leader of the Developmental Therapeutics Program and Chief of Melanoma, Roswell Park Comprehensive Cancer Center
• - Anatomic Pathology - Senior Vice President of Scientific Development and Integrative Medicine - Roswell Park Comprehensive Cancer Center

When: June 25, 2020. 3PM - 4PM EDT

Where:

This live event will also be recorded and transcribed for use by media and communicators after it is concluded.

Thom: Welcome to this 麻豆传媒 live expert panel we have with us three panellists to talk about cancer doctors and cancer researchers pitching in on the fight against Covid. These professors and researchers are from several different cancer centres. I'll introduce them in just a moment, and they're going to talk about how ways that cancer research has enabled them to start looking into what possible treatments there are for Covid as well as other topics related to that, and I want to go ahead and make a couple introductions. 

So, we have Dr. Igor Puzanov. He's Professor of Medicine, and he's also director of early phase clinical trials. And co-leader of the developmental therapeutics program, and chief of melanoma at the Roswell Park Comprehensive Cancer Centre. Quite a lot of duties you have their doctor Puzanov.

We also have Dr. Carl Morrison. He's in anatomic pathology ad he's also Senior Vice President of scientific development and Integrative Medicine at Roswell Park Comprehensive Cancer Centre. 

And last but not least, we have Dr. Roy Jensen, Director at the University of Kansas Cancer Centre and director of the Kansas Masonic Research Institute. Thank you so much for joining us panellists. And I want to start with Dr. Puzanov, if you're ready for us and ask you to tell us about why cancer researchers have joined this fight against Covid. And what unique insights from cancer research do you feel can be applied to the fight against Covid?

Dr. Puzanov: So, the cancer and infection have a lot in common, it's the processes involve the immune system and the inefficacy of the immune system to actually clear either the cells which went into the cancer pathway or the viruses or bacteria, which are kind of breaking through. So, the background in cancer immunology, we know actually prepare some of the researchers in the oncology world well to kind of weigh in on the Covid or other emerging infectious diseases of the time. 

So, from that background, it was only natural that our Cancer Centre got involved into the Covid situation pretty early actually in late February or early March, because the other part of the oncologist, means that we are connected in a worldwide - we have seen actually the situation was getting dire in Asia, in South Korea, in Europe, Italy, and also before eventually came to US, we have been aware that it's come in and we know about the nature of the threat. So that's why we got involved.

Thom: Thank you and tell us a little bit more about this immunotherapy research and how findings from cancer studies about using different molecules to stimulate the immune system to potentially fight cancer how that translates to fighting a viral infection like Covid.

Dr. Puzanov: Yeah, so, there are some similarities and some dissimilarities, but in general, the immune system should detect any danger and clear it before it becomes so fatal to the organism. And when you think about cancer - cancer usually means that somehow that first line of innate immune defence - meaning like the natural immunity, we all have against, big threats which we inherited from our ancestors got broken through. And that same innate immunity actually protects us from major pathogens like tuberculosis or gram- negative bacteria, or actually pieces of DNA or RNA which don't belong to our organism that's to the system both like receptor system which actually led to a Nobel Prize for the researcher at UT Southwestern and so this is one part and the other part is the adaptive cell immunity, which is the second in line and kind of picking up pieces from the first line of defence and developing specific antibodies or T cells we are all familiar with. And when I say T cells - that’s the same cells which are being influenced by checkpoint inhibitors, like Keytruda, Opdivo and others, we all know are used to fight cancer. 

So, there is that connection between immune system cancer and the virus - and to be more specific, with this virus you have two problems. 

One problem is actually inability of some people to kill the virus immediately upon arrival, like you kill it right away, using probably the innate immune system. If it's very strong, you will never get infected at all – not even asymptomatic - you simply don't get infected. 

And then the second line is that some people actually kind of harbour the virus, the virus doesn't go away, they're unable to get rid of it. And as it's kind of in them, they enter this vicious cycle of being more activated, more activated, and finally, their immune system enters what we now call the cytokine release syndrome - cytokine storm, and that's actually overactive immune system which is ineffective. It's not killing the virus and it's actually damaging the host, damaging the patient. So, you have several options to enter the cycle of the virus and intervene using actually some of the immune system paradigm we have learned along the way. So that's the that's kind of in general or high overview of that selection.

Thom: Thank you for helping us understand that. Dr. Puzanov. 

I'd like to ask Dr. Morrison if you can tell me your thoughts about why you feel it's important that cancer researchers have joined into this fight in what, what particular skills and knowledge they have to offer?

Dr. Morrison: Yeah, I’d kind of like to emphasize a bit of what Dr. Puzanov was saying about the immune system. I think to layer more additional details on top of that, one thing we've always been very accustomed to in cancer is that there's a lot of heterogeneity and response. So, two, three people can get the same cancer and one will have a very dismal outcome and one will have a great outcome and one will have a moderate outcome and I think we're seeing the exact same thing with the Coronavirus and the Covid-19 epidemic- pandemic, and out of that has sprung a whole new area of medicine that's referred to as precision medicine and while precision medicine or explaining the heterogeneity of response to either some type of an assault on the body. While it is, it had been discussed and used in many other areas of medicine, it is by far and away, cancer and cancer cure has been the leading poster child for precision medicine. And at the front of precision medicine - it is what they could refer to as molecular techniques. Right? How do we interrogate the immune system and one of the more common ways that we're doing that today is using a really sophisticated toolset called next generation sequencing to locate these various immune cells that are actually the policemen of the immune system and from that, I think   that we've been doing it for quite some time in cancer, and if making that same type of an application to viral infection - it could make a difference.

Thom: Thank you, Dr. Morrison. Dr. Jensen, I'd love to hear your thoughts about what it means for cancer researchers to pitch in on this fight and how your centre is responding to the pandemic itself.

Dr. Jensen: Sure, can you hear me okay, Thom? Very good.

So first of all, thank you for having me on the forum and what when the pandemic hit, particularly Washington State in New York City, we could clearly see that it was heading our way. And so back in February, we started planning for this event and discussing how we could depopulate our clinics, how we could delay screening and other approaches to our cancer patients, and to specifically look at who could work from home. And so, when the decision was made on March 16th, at our institution to kind of shut shelter at home and shut things down as much as we could, we were ready. And that was a tremendous benefit to us to have that week to 10 days to get ready with and that was clearly not available to folks in either Washington state or on the east coast and so we were very thankful for that. 

But like I said, one of the first things we did was to figure out who did not have to be in our cancer clinic over the course of the next two months and who could we delay, follow up and who could we switch to telemedicine? Who could we switch to oral medications and all of those things were a critical part of our response trying to prioritize patient safety first and then to see how successful those strategies were.

Thom: Dr. Morrison mentioned precision medicine as part of the work that they're doing at Roswell Park Comprehensive Cancer Centre, I want to ask what other kind of precision medicine is happening there at the Kansas Cancer Centre.

Dr. Jensen: So there's a number of things that are ongoing, we just opened a new clinical trial and in partnership with a St. Louis biotech company on a MK two inhibitor and that's basically an inhibitor or a component of the MAP kinase signalling pathway, which controls the production of a wide variety of inflammatory cytokines. And so, the idea is that we could selectively down regulate the expression of all of those proteins that are stirring up the inflammatory response to the virus and keep people from progressing to adult respiratory distress syndrome when they had a severe infection and we're just now in the process of opening that trial up.

Thom: Thank you.

Dr. Morrison, can you tell us a little bit more about your precision medicine work and especially the biomarkers that you're looking for to try to identify which patients may suffer more severe cases of Covid versus which may not and how we can perhaps determine that earlier on when they're diagnosed?

Dr. Morrison: Yeah, let me go back to - I'll try to put this in maybe simplistic terms, right, but we were talking about, the immune system, protecting your body, right, and they're basically two types of policemen in the immune system, we refer to those as B cells and T cells. And each of those B and T cells that are in your body, or each of those policemen that are in your body are no different than all the policemen today that are in a major city, that each person is a little bit different. Okay? A little bit different, right? And if we were to say, well, how could you tell when something - a really big event was occurring in that city? And the way you could tell is that there'd be lots of policemen there, and lots of those policemen would be different. They're different from each other. Okay? So, we're basically taking that technique, that technology called next generation sequencing, and we're looking to say, how many policemen are showing up at the Coronavirus attack and are all these policemen different? Because if we know if there's more different policemen and firemen and everything there, we refer to that technology as convergence, and we're actually using that sequencing of the policemen’s DNA, each policemen’s DNA to say, are there a lot of them there? And are they exhibiting what we call convergence? Therefore, we know it's a big event, and it'll get me treated. And if you look at perhaps one of those people who are having a poor outcome with the Coronavirus, it's very likely, right, that's what's happening. They have policemen showing up, but just not that many different policemen. So, it's not a big event for them. And if we go through this, I think we'll find it - there's not just two types of infections with Corona viruses, there’s probably multiple types, right? As we know, some people are asymptomatic, right, particularly younger people, and there are some people that get typical flu like symptoms and then- if you remember there was one family in New Jersey, four members that ranked in age from I think early 40’s to 80 years old – they all died in one week, right? It's telling you that there's something that's common among our inheritance and our immune system that is preventing or fighting the Coronavirus.

Thom: Thank you for much for that explanation and helps a lot to understand what it is that you're looking for.

Dr. Puzanov, with regard to convalescent plasma, there's been a lot of information in the media about this. I've even seen a kind of public service campaign featuring movie stars and celebrities and athletes, saying if you've survived Covid call this number to learn how you can donate your plasma to research what's being done at your centre on convalescent plasma.

Dr. Puzanov: So, we have Dr. George Chen in charge, he is a bone marrow transplanted - so it’s his specialty to collect the plasma in cells and ever since the beginning we joined with Mayo Clinic and started collecting convalescent plasma. But like Dr. Morrison alluded to, we have been fortunate not to have that many patients. I think, overall, we have seen only 18 patients, with Covid overall, between March and now, or maybe a little bit more, but not that many. So, while we collected one record, and because we didn't have any cases, we actually are sharing that plasma with regional centres, because they needed more than we do. So, yes, convalescent plasma may be good. And as you now know, there are studies won by Eli Lilly and one by Regenerons, where they actually use those antibodies against the virus and they isolated those antibodies from the plasma, and they multiply them and now they are using them in clinical trials, I think there are some believing that this could be one of the most important pathways to attack the virus - with the - simply multiply the best antibodies, you can isolate from these random plasma centre, plasma samples and optimize them and then make them in large quantities and give them to patients when they are early in development of Covid syndrome, when they are just infected, because it will prevent ideally, the entry of the virus to that spike protein - that little spikes on the surface into the lungs of the infected individual or other organs. So that could be actually very, very good. And although not a vaccine, this will actually do. 

So I like this line of research and I think it's very promising and yes, if people did go through the disease, it is kind of wise to call the local Covid hotline and say - I would like to go, maybe you need me, because you may actually have some special gift for somebody who may actually need it and there's a lot of cases outside, we are New York, so we were early but now all the cases are rising elsewhere. So, I think it's still important to be on our toes and contribute to other people's care.

Thom: Thank you, Doctor Puzanov. 

Dr. Jensen, there have been a lot of recent reports that cancer diagnosis - new cancer diagnosis have been way down due to patients potentially being reluctant to come to the doctor. Go to the hospital for screenings, been reports of rises in death from stroke and heart attack heart attacks as well while patients stay at home and avoid going to the hospital. What concerns are there that patients may present later with more advanced stage disease? And what do those numbers kind of signify to you and what can be done to reassure them that they can safely come and see their doctor in spite of the pandemic?

Dr. Jensen: Well, Thom, you highlight a very important issue. And in fact, Ned Sharpless, the director of the NCI just had an editorial this week that the data that he looked at suggested that as many as 10,000 Americans may wind up dying prematurely of cancer over the course of the next decade as a result of the interruption of screening and prevention services, during this pandemic, and so - you really highlight a hugely important issue and we've been working awfully hard to make sure that our patients understand that this is a safe place to come. Knock on wood. We have not seen any transmission of the virus to any of our healthcare workers. We have started a program of voluntary testing for Covid among our faculty and staff to assure our patients that our workforce is safe, and this is a safe environment. And, we've completely redone the way that we practice medicine to make sure that we're engaging in social distancing, and PPE. And one of the luxuries that we had at our institution is that there was never a PPE crisis here. We were always able to stay ahead and so we never had either faculty or staff without benefit of appropriate PPE. And I think that's been a key thing to limit transmission of the virus.

Thom: Dr. Morrison, you talked about precision medicine and research into determining patients having less severe or more severe cases of the disease. Are those kinds of techniques also applicable to determine what treatments might be most effective as it is in cancer?

Dr. Morrison: I'd say there's probably a more complicated question, but certainly you can't ignore the fact that treatment is associated with response and we've definitely seen that two people getting the same treatment with the same disease and a different result. I definitely think that is - as we move through this process, we will be able to compare people who got different treatments, that had the same immune background, and perhaps sort out what is the better treatment based upon what your immune cells look like in your body? And I think that's a realistic hope that we will get to, but we're, I think we're a considerable amount of time away from that, we will probably fully be within a vaccine before we reach that point with precision medicine Covid buyers – I would hope so anyway.

Thom: Doctor Puzanov, tell us about some of the other drug trials that are underway at your centre and what those drugs, what class of drugs they are and what they might potentially do if found to be effective.

Dr. Puzanov: So, like right now we have randomized trials for two drugs, which actually,  , met their primary endpoint – Dexamethasone, which is actually an old drug, is very cheap, about $5 or less a day, six milligrams daily for 10 to 14 days, actually improves survival of patients with both moderate or severe Covid, meaning like patients who are on at least some oxygen requirements. The death rate went from 25% to 20%. So relative improvement - 25%. And then for the intubated patient to really severe, the critical Covid patients, it went from, like 44 to 38%. So, that was actually like 130 - no decrease, relatively speaking. So that actually is the only drug with a statistically significantly improve survival. The remdesivir people talk about a lot actually didn't reach statistical significance for overall survival, probably because the study was stopped early because of different considerations and the need to have some drug available. So, we have two drugs, the remdesivir seems to be working better early, in the lighter cases. It makes sense because it's an anti-viral, so you will kill the virus. The dexamethasone is actually kind of calming down the cytokine store. So, it's working better actually in the severe or the critical cases, which again makes sense, because you are not actually killing the virus at this point. You are just calming down the patient's overactive immune system. 

And those are the two drugs we have confirmed. 

The other drugs are under investigation. Dr. Jensen mentioned the Mk two inhibitors, the other interesting drugs would be jak two inhibitors, again the master switch of different cytokine production, bruton kinase inhibitors, whether it's a tele Bruton at trial with estrogenica and NIH - we almost did a trial, but again ran out of patients before we could start and then the Ohio State is actually doing a Bruton – the kind of the original bruton kinase inhibitor and multiple people are doing multiple things, which of course brings out the question whether any of these studies can be finished successfully, and show off the data – launch the IL6 inhibitor – tocilizumab as well as Sarilumab are under investigation, again counting the cytokine storm - but it's a lesson to be learnt. We were kind of surprised, we did what we could, we are still doing what we can to develop effective drugs for the disease and hopefully vaccine. 

There are some ideas of course for specific vaccines, we all know about the operation warp speed, so we like a lot of speed there. 

Five companies were selected for that and, and then the other people trying to develop vaccines. The one caveat I will say about vaccines, with HIV virus, which is different, I give you that, people talk about vaccines since 1985 and it's 2020 - we still don't have vaccine. There is an interesting idea actually to repurpose some old vaccines like a TB vaccine or oral polio vaccine, with the idea that if you are exposed to the live attenuated virus, you may actually boost your innate immune system, and there are some theories that in Eastern Europe, specifically, where people who are vaccinated with either TB vaccine or live polio in the old days, that the death rate seemingly is lower in those countries from the Covid. So people are bouncing around ideas, and I have no doubt that we learn a lot from this, and I really commend Dr. Jensen and his leadership, as well as our leadership for actually not underestimating the crisis and being ready with a lot of PPE’s and ventilators and our support for the staff because supportive care actually matters a lot in this disease as well. And yeah, yeah, well, that's what I would say. So, remember the dexamethasone and remdesivir are two drugs approved by FDA with proven data right now.

Thom: Right. Thank you, Dr. Puzanov, from what I understand about the reports on the dexamethasone increasing survival being as a steroid, I believe, helps to support the respiratory system in spite of the infection so that the patient doesn't have their oxygen level drop significantly. Is that right?

Dr. Puzanov: So basically dexamethasone is anti-inflammatory drugs so it's actually affecting the same pathways like Tocilizumab, or Sarilumab or the Jak two inhibitor or possibly MK-32, because it dampens the immune system, dampens the inflammation, dampens the production of the cytokines and it does it at fraction of the cost of anything else because the whole thing costs like $5 Instead of 5000. Pretty amazing actually, and you can give it by mouth. So if you are able to take oral medications like if you are just let's say on five litres of oxygen, just sick, but not like sick, sick, like deathly sick, you take your dexamethasone and after a couple days, if you feel better, you can go home and finish the pills at home, this is really good. This is really important trial. 

And the other one I would point to you, like Dr. Morrison mentioned the genetics, and all kinds of differences between individuals. So, there is The New England journal paper actually from the New York Memorial group and others the GWAS group, the genome people and they found some connection between a block site A - been 45% more likely to suffer severe Covid, block size zero actually 35% less. 

So, like if you will have zero or A, the age has doubled the risk - so there is some connection there and they found some other possible connection. So, there is some interesting things to tease out about the genetics and inheritance, because it is really strange for some families, three, four individuals die, and then you have populations where the Covid seemingly is not as deadly as some other situations. 

So, a lot of this going on and we at Roswell are part of the global virus network, Dr. [inaudible 28:39] of Global Virus Network Outfit. 

So, I was on a call this morning at six o'clock – we have everybody calls around the world with Singapore, China - you name it, South Korea, Italy. And we discussed the efforts which are going on around the globe. 

It's a very impressive actually, on all the different thrones on all the different points in that continuum of care for patients with Covid, there are a lot of efforts going on. So, it's great to be really actually at the end positive for science and for preparement for these threats. We haven't had a threat for 100 years. I think if it comes next time, there will be a totally different ballgame in place.

Thom: Dr. Jensen, you mentioned success at your centre in avoiding transmission from patients to healthcare workers and staff. What measures have been most effective in that and what does that tell you? Or what should that tell the public about the importance of things like masks and social distancing?

Dr. Jensen: Sure, I would say it's hard to say which intervention has been the most effective because we implemented a broad number of things simultaneously. So, it's not like we did a controlled study trying to figure it out. We were essentially adopting an all hands-on deck approach to try everything that we possibly could. I'm quite certain that tailoring the PPP to the situation for instance, there's kind of a higher level of PPE called a PAPR, which is appropriate for when you think you may aerosolize the virus - say like doing a bronchoscopy exam, and as you might expect that has a tendency to generate quite a few droplets and aerosols, whatnot. And so, folks doing those, it's critically important that they have on the highest-level PPE that that we can get them. 

If you're just in a more normal clinical setting where you don't expect that you'll generate those kinds of things, I think a normal surgical mask or an N95 mask and other situations is certainly appropriate. 

So I think being able to tailor that, you can't wear a PAPR to every single interaction with somebody because obviously that is much more expensive and there's limitations on the availability and so I think trying to make sure that you're appropriately gowned up for the situation that you expect.

Thom: Can you elaborate on a PAPR?

Dr. Jensen: So, it essentially, kind of creates a controlled airspace. It's sort of like a little bit like a helmet that prevents - that controls your exposure to any aerosols that that would be in the room when you go in to do the procedure.

Thom: Gotcha. So, it's something that the physician’s kind of like wear.

Dr. Jensen: It's kind of like a bio suit, essentially for the head. Yeah.

Thom: Gotcha. There's been a lot of discussion about racial disparities, revealed by the impact of Covid. And there's a lot of similarities with those kinds of rates with other diseases as well. And I wonder what your thoughts are about that and what you're seeing in your work and your research and how big of an impact those racial disparities are with cancer and with other diseases as well and what you think needs to be done about it?

Dr. Jensen: Well, pretty shortly after the pandemic hit, it became clear that this is a huge issue, and you don't have to look any farther than places like Detroit or New Orleans, New York to see that African American populations, Hispanic populations, folks in lower socio economic status and high levels of chronic disease were significantly greater impacted by this virus than other groups. And just an example from our place, the death rate for African Americans that test positive for the virus in our area is five times greater in African Americans - five times greater. That's a stunning - just make your jaw go slack statistic. And so, it's very clear that this virus has exacerbated those types of disparities issues almost more so than in practically any other situation that we can point to.

Thom: Thank you, Dr. Jensen. 

Dr. Morrison, I'd love to ask you to explain a little bit more something that you mentioned earlier using next generation sequencing. This technology that I understand is part of these kinds of precision medicine studies. What exactly does that enable and how is it different than what maybe was available in a previous generation and where, where that's helping you go in and how you do this research?

Dr. Morrison: Yeah, I think that question is also relevant to the disparity issue and the fact that genetically, only 1% of our DNA is different between one individual and other one, but there are certain racial differences in our DNA, and it could account for some of the severity of infection that we see in African Americans, and perhaps it's not just related to the socio economic issues. But if we look at how do we investigate that - the technology called next generation sequencing, and what that enables us to do is sequence - your DNA is it made up an alphabet code, and it's a very simple code, it only has four letters, right? But it's arranged in all these various combinations and across short regions and long regions. And prior to really, about 2003 -04 we basically could only look at very small regions of your DNA. In other words, maybe 150 or 200 base pairs at a time. And if you if you stopped to think about this alphabet, if you took the DNA in any one cell in your body and said, well, let's make the alphabet as big as it could - as something that's in a newspaper. If you stretch that out, it would almost reach the moon. Okay. 

So, you understand that if we were just looking at this, if we were trying to read that newspaper one line at a time, as we were doing 15 years ago, we would never get there. But then a technique sprung up and that technique was really called second generation sequencing and over the years that terminology was transferred to next generation sequencing, that will then enable us to basically read all those letters at the same time. And it's just been transformative in cancer care, it has just really made it's - it's now become in many disease types like lung cancer, the first hook tool you reach for to say, how should we treat this patient? And hopefully we will get that way with the Covid virus and susceptibility and it'll have impacted disparity, we'll be able to look and say, is all this difference in racial inequality just due to socio economic status, or is there some genetic reason or some component of it that we need to tease out?

Thom: And when you identify what that what that genetic code tells us, does that influence for example, how the patient's T cell and B cell receptors function that you were talking about earlier as part of some of your studies.

Dr. Morrison: So somewhere along that string of alphabet from here to the main, there's a little stretch in there, that's - if it was from here to the moon, it'd be one little stretch that probably lasted maybe a mile or so, that determines how B cells work and another little stretch, it's a mile or so that determines how t cells work. And yes, we definitely need to stop and look at those areas with extra special attention for stuff like Covid virus infection.

Thom: That's such a great explanation. I wonder at a mile - what size font is that? I'm only kidding, of course. 

To Dr. Puzanov, I'd like to ask if you could help for us to explain how different studies are looking at treatment for Covid and how that differs from trying to solve severe cases versus trying to prevent the patients from developing severe cases to begin with - something you mentioned in the discussion of dexamethasone has been found in a study to be for very severe patients, improving survival. What are some of the different studies looking at in terms of both of these ends of the spectrum, preventing the onset of the disease from the start versus helping people to survive severe cases and why are both so important and help us to tease out what some of those mysteries are a little bit more?

Dr. Puzanov: Yeah, this is really important. So early you want to prevent the virus to enter your body – period. So, the early study will be actually concentrated on killing the virus with anti-viral medicine like a remdesivir or boosting the innate immune system like a study we actually developed as Roswell - combination of interferon - interferon actually is a natural occurring protein our bodies make, and it’s called interferon because it interferes with infection or by viruses. It was found on that basis, so interferon plus actually a drug called rintatolimod, which is a stimulator of the toll-like receptor, meaning like the first defence on the macrophages and neutrophils or intimate or the inherited - kind of the first line immune system defence. 

So, we hope that for patients with cancer and early Covid, we can boost their immune system enough so they can actually clear the virus quickly. They never develop any severe Covid and case closed. So, this is the study, this is the hope, it's by no means assured, this is the idea of early studies. And you can imagine there are 1000 companies who are trying to develop a specific anti-viral drug, doing these large screens, that's actually part of our global virus network. We talked to a team in Australia, which basically, they have this level four facility - means like the most secure or the most stable facility, where you can actually study these deadly viruses, like Covid or SARS or Ebola, and they pretty much have like a black box and they put a virus in and they just throw like thousands and thousands of different components on like a screen and whatever kind of kills it they take for further investigation looking for that early hit. 

So that's early.

And then what happens late? Well two things are happening late.

One, there is the cytokine storm. So, these are the drugs actually calming the overactive immune system like possibly the MK-2 that Dr. Jensen mentioned, like Bruton Kinase inhibitors, like Anti-IL6 receptor, tocilizumab or and or Sarilumab drugs and JAK2 inhibitors, they possibly complement inhibitors as well. And then, the patients if they don't actually get better with a cytokine storm, they kind of enter this last phase with a lot of blood clots, a lot of immune collapse and believe it or not, actually, those T cells express a lot of PD1 – Programmed Cell Death receptor one and the PD1 inhibitors which I used in cancer -  like Opdivo, Keytruda, others – you name it - they keep [inaudible 42:17] we actually had this idea early with Dr. Asherko, in Italy, in Naples, but the problem with these anti PD1 drugs is that one of the side effects is inflammation of lungs, so people are kind of afraid that - are you going to help? Are you going to hurt? So, one really good piece of evidence we are looking for is - and where actually cancer patients can help us all. A lot of cancer patients in all cancer centres, including Kansas, including Roswell, including others are on checkpoint inhibitor. And we really are trying to tease out if you are having cancer and you have high risk of having severe Covid and dying, we now know that. But what if you have cancer and you are on checkpoint inhibitor, how does this affect you? Know your fate. 

And if it turns out that if you have cancer, but you are on checkpoint inhibitor and it turns out that you actually end up better off than average population or average population of cancer patients, this may suggest that actually the checkpoint inhibitor may play some role in either preventing Covid or preventing severe Covid. But we need some evidence because, it is risky, and you have to always - do no harm – patient’s safety comes first, and these data are being collected and analysed. There was a Lancet paper by, led by Jeremy Warner from Vanderbilt, my old alma mater, and Elizabeth Griffith actually was one of the co-authors, and they analysed over 1000 patients and they have seasoned out the data and I'm really, really waiting for it because if it turns out that checkpoint inhibitors may somehow boost the immune system, then that would be another kind of pathway to attack Covid and help the patients who so desperately need to?

Thom: Thank you Dr. Puzanov and I want to ask you to elaborate on one aspect of something you mentioned a moment ago. I just want – one more reminder to our media in attendance, if you have any questions, please do chat them to us and we’ll squeeze them in, we have a little bit of time left with our panellists so please do send those questions in if you have any, and Dr. Puzanov – you mentioned targeting the programmed cell death receptor. One thing that I understand about that from reading recent research myself is that, that can sometimes lead to adverse responses from the patient and that kind of reminds me of talking to one of our panellists recently about developing a vaccine that could also have a boosting effect to the virus, if the vaccine isn’t effective. 

How are those kinds of things potentially screened for and tested to determine that these kind of treatment options are safe and don’t add to the effect of that cytokine storm that is leading to death in Covid cases for example?

Dr. Puzanov: So, I would start with the checkpoints. So, if you think about it – during a trial if you worry about the side-effects – and we do, your point is valid, people can develop other immune inflammatory side-effects from checkpoints. The first thing you would do actually – you would look at patients in life, in this case – cancer patients- they already are on checkpoints to fight the cancer – they have cancer, you worry about Covid, and you would compare that group to a controlled group of patients who are not on checkpoints, and you ask yourself a question. Is the patient group on checkpoint more or less likely to get Covid, and if they do get Covid, are they more or less likely to get severe Covid with inflammation – yes or no – and if the answer is yes and yes – well then checkpoints are probably not the way to go, because if you are on checkpoints that really work, you already have – you don’t need to do experiments. You already have data. If you don’t see that and if you see some protective effect – because the numbers we can actually see that, then you can say you know what – these patients never get Covid. How come? And they don’t get severe Covid and they don’t get these side effects – maybe – maybe it’s safe and then of course you have to do the study and the way to protect the safety – you start with one patient, you follow that patient, then you add two more, then you kind of slowly add more patients, not in like a big way – so if you actually have a side effect, you will limit that downside, you will limit – the same goes for your other question – any time we do a study, if you worry about side effects like in the study we do at Roswell – Dr. Kalinski and Segal - the combination of the interferon and Toll Like receptor, inaudible 47:19] Rintatolimod, you may start with actually one patient, then we will add two more – watch them. Then we will add three more at higher level, then three more- and any time anybody gets anything – we analyse it and if it doesn't feel safe, we just – go lower and adjust it. This is what I actually do for a living. This is the phase I clinical trials, the early phase clinical trials you mentioned – this is actually my specialty and that’s when you take the drugs from the laboratory, from the research and you start giving them to patients. It’s really important not to harm the patients. Do no harm is our mantra in this field. And it should be.

Thom: Thank you Dr. Puzanov. So many mysteries to unravel and so much nuance to the way this disease is unfolding and all of your work is so much appreciated and your explanation of all this for our panel today. With that we’ll go ahead and draw to a close, I just want to remind folks in the audience that we’re going to have a recording and transcript available and if you registered, you're going to be on that list to get that information. If you didn't register send us an email to [email protected] and we’ll make sure to add you to that.

With that, thank you to Dr. Jensen at the University of Kansas Cancer Centre, thank you Dr. Puzanov and Dr. Morrison with Roswell Park Comprehensive Cancer Centre, thank you to the communications offices at both cancer centres for helping us to coordinate this panel, and with that I will say thank you to everybody – stay safe, stay healthy and good luck.