Developing New T Cell Immunotherapies for Difficult Solid Tumors: Prof. George Coukos, Department of Oncology UNIL-CHUV

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 0:00

You unleash the power of a natural immune response with hundreds of different clones that attack all sorts of things in the tumor.

Alex Jani, X-Health.show: 0:13

Hi, I'm Alex and welcome to the X-Health.show where I talk to visionaries behind the latest innovations in healthcare. For the eXtra health of the future. We're at the Swiss Oncology and Hematology Congress in Basel, Switzerland, where my guest had a presentation the day before. Professor George Coukos is on a mission to find a cure for the most difficult cancers. He leads major oncology research institutions in Lausanne, Switzerland, to develop novel T cell therapy approaches for solid tumors. Trained as an MD and obstetrician gynecologist, he studied cell biology and oncology, which led to the discovery of spontaneous anti tumor response in ovarian cancer. He developed combinational immune therapies that have been approved for lung, liver and kidney cancers. You'll hear about how tumors suppress anti cancer immune response, supporting T cells to find solid tumors, TIL therapies, Adoptive T Cell Therapies, and autologous dendritic cell vaccine. Please note, we're talking about treatments that are in the early research stage, so unfortunately not yet available to patients outside of these clinical studies. [INTRO ENDS] George, at the BioAlps networking day you showed two PET CT images, one: multiple metastatic melanoma patient and two: the same person free of metastases. What happened between these two images?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:42

This was in the context of clinical studies that we were trying – tumor infiltrating lymphocytes, I will call them TIL therapy in patients with advanced therapy resistant metastatic melanoma. This was a typical patient who is at the end of line and has basically exhausted all the therapeutic options.

Alex Jani, X-Health.show: 2:05

Which are: chemotherapy, what else?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 2:07

Well, not chemo but immunotherapy. So in the form of PD-1 blockade, CTLA-4 blockade, and for those who have a BRAF mutation also kinase inhibitors, like BRAF, MEK inhibitors, and other lines that clinicians like to use, like a combination of PD-1 like Pembro, with anti angiogenesis agents, radiation, localized surgeries, and all sorts of things that doctors try to do in order to keep the patient alive. We got these patients really at the end of line, and they had typically received anywhere from three to five prior lines of treatment. The life expectancy of this patient – you would expect to be less than a year and the average is about six months or so, if they have no additional treatments available. So we offered them a therapy using their own tumor from where we extracted lymphocytes and expanded those lymphocytes in culture in a dedicated laboratory in the hospital. And then we gave them back basically tens of billions of their own lymphocytes. And what this is, Alex, is really a sort of an immune transplant. Because we prepare the patient with high dose chemotherapy, which is sort of a light transplant regimen, it does not eliminate the bone marrow completely, but it creates space in order for the new cells that are coming in to be able to expand. Over the course of the next two to three months in this patient, the cells that originate from the tumor will expand and repopulate the whole body. You have a reorganization of the immune system with very strong anti tumor immune response. We basically amplify by thousands fold the immune response against cancer by this therapeutic maneuver. And what we have seen, as reported also by other international investigators, is that, in fact, a proportion of these patients will respond and some of them will achieve a complete response. This is one of the patients I showed. The remarkable thing is that once a complete response is achieved, then the chances for cure for this particular patient are extremely high. We're talking about, with long term follow up, over 90 to 95% disease free out at several years, which by all accounts, clinically speaking, is a cure. This is in patients who really had no therapeutic options and comparing these patients to patients who don't receive the TIL, you see a very significant difference in the survival. So we are very, we're very pleased. This really opens new prospects in designing therapy for patients. Now, one needs to understand, this is a completely personalized treatment and what we call in in medical jargon is autologous, which means that it comes from the patient's own cells. This is this is what I wanted to ask now about, if you could explain the TIL therapy. What is it made off – you already said it's from the patients' tumor cells... It is built on, let's say, 30 years of discovery work in many tumors, melanoma being the leading disease, but all solid tumors, turns out, are following suit in a very similar way. In a proportion of patients, we have T cells, or lymphocytes, infiltrating the tumor spontaneously, and some therapies increase that, but there is a spontaneous immune response that can be detected already at the time of diagnosis, in patients who have not received any prior treatment. These lymphocytes, it turns out, that in many cases are specific against tumor. There is an attack of the body against the tumor. And that's what we harvest. We really go to the tumor, we harvest these lymphocytes, and then we expand them with methodologies that have been developed over the course of the last 20 years. We start from a few thousands lymphocytes, or maybe a million or two, and we end up with 50-200 billion lymphocytes at the end of that culture. During that expansion, there is also profound reprogramming of the cells. Now these cells acquire new vigor in terms of fighting cancer and when they go back into the patient, they find the tumor, they infiltrate the tumor, and in the luckiest cases, they eliminate it completely. Or they slow it down, so we call it a partial response.

Alex Jani, X-Health.show: 7:15

You cultivate the cells, these millions of cells outside of the person's body...

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 7:23

That's exactly right.

Alex Jani, X-Health.show: 7:24

... and then you inject the cells back to the body, and they do the work. Can they still multiply themselves?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 7:32

Absolutely. Once you inject them, you're talking about at best 100 billion cells, but the body has approximately in a steady state– over 3 trillion lymphocytes. So over the course of a week or so these lymphocytes will continue to expand to fill the whole space. What we see is in peripheral blood and in the tumor after the transfer, the lymphocyte profiles look very similar, because it's the same lymphocytes that originally came from tumor and now they populate the entire patient. These are the life saving lymphocytes, which we have now expanded to very high levels.

Alex Jani, X-Health.show: 8:16

It sounds miraculous, and I'm so happy that this is science.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 8:21

It is but you know, Alex, this took 40 years of development. Steve Rosenberg started this work in the early 1980s, publishing the first paper demonstrating the principle of this being, correct. Of course, no one believed it. And then 20 years later, he published the first clinical evidence that this can work. It took 20 years for that particular group to develop all the methods that were required, both in terms of expanding the cells properly in the culture but also preparing the patient in the proper way in order for the cells to work when they are infused back. What one should really point out here is, clearly we owe this to his perseverance and his faith in this that this was going to work. But we also owe it to the institutional leadership at the National Cancer Institute, which continued to fund this kind of work, a very high risk work, even if it wasn't working and the first clinical results weren't promising. They continued to fund him in order to be able for him to do his work and well enough, 20 years later, he got it to work. Now, one needs to point out that this started in melanoma because the community, including Steve Rosenberg, who is a very dear friend, at the onset of this believed that most tumors are not harvesting tumor specific T cells, but it's mostly melanoma and a few other tumor types that do that. Later, thanks to the work of many laboratories, including ours, when I was at Penn, we actually put forward the notion that most tumors actually have a spontaneous immune response.

Alex Jani, X-Health.show: 9:02

We should all thank him for his persistence. I mean, 20 years, no one believes you. Probably there was some people starting to believe in him on the way when he showed new evidence. Can we speak now about your research? Because you actually discovered the spontaneous anti tumor response in ovarian cancer?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 10:30

That's correct.

Alex Jani, X-Health.show: 10:31

How did that happen?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 10:33

When I started my lab at Penn, we really wanted to focus on ovarian cancer and the leap of faith was that there was going to be an immune response against ovarian cancer, and we could leverage that immune response therapeutically. Well, that was a far fetched idea at the time, because clearly no one believed, including my colleagues at Penn, that this was going to be true. We started working both at analyzing T cells in the tumor microenvironment by staining and molecularly in the tumors. All this evidence indicated, in fact, that at the time of diagnosis, there is a spontaneous immune response in some patients, not all, about 30 to 40%. But when this happens, you can clearly see it under the microscope and there is molecular features that denote an attack and an activation of the immune system. When these happen, these patients get to live a lot longer. They are the only patients we found, who live a long time and may have a chance, a small chance to get cured.

Alex Jani, X-Health.show: 11:43

What does it depend on? Do you know, what does it depend on if the patient actually has these in themselves or not?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 11:52

It's the interface between the tumor and the host. What it depends on is, on the one hand, the host has to be immunologically competent and so there are some people who have a better immune response than others. Most importantly, the tumor must be immunogenic. It must present antigen or must present proteins and peptides that the immune system can detect, and must produce a micro environment that is conducive to immune attack. Almost two decades later we identified the molecular underpinnings of that in ovarian cancer, and it has to do a lot with DNA damage. So Homologous Recombination Deficient ovarian cancer or BRCA-mutated ovarian cancer, it turns out, that is spontaneously inflamed. Because of the inherent DNA damage that the cells have, they trigger a process that we call DNA sensing, which is cell intrinsic in the tumor cell. That's kind of tied in, locked in in the molecular underpinnings of that cell becoming cancer. The first event is DNA damage and BRCA loss, and inability to repair DNA – that's the first step for that cell to become cancer. But that very moment, that very event leads to DNA sensing and activation of the machinery of the cell that creates an inflammatory response, particularly producing interferon. This molecular pathways have now been dissected very carefully and one talks about sting activation and so forth. The tumor cell produces itself interferon and that allows the immune system to catch it. It becomes a battle between a tumor that runs and the immune system that follows – it's a sort of a catch phenomenon. But in most of these patients, of course, whom we diagnosed with advanced disease, evidently, the immune system hasn't been able to clear the tumor. But it's there.

Alex Jani, X-Health.show: 14:14

And you can support it now.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 14:15

And now we can find ways to activate it and leverage it therapeutically, yes.

Alex Jani, X-Health.show: 14:20

What are the options that we have to activate this system that already is there?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 14:30

This biology is almost universal across all tumor types. We discovered it in ovarian cancer but later on people reported that in all tumor types. The first obvious consequence of that immune response being there is that one can activate it with drugs. This was the premise for the immunotherapy drugs to be developed. So anti-PD-1, anti-CTLA-4. Not just in melanoma but across all solid tumors. And today, anti-PD-1 particularly and all the series of drugs that follow, have shown efficacy in the majority of tumor types different from tumor to tumor. But we know there is a proportion of patients between 10 and 20% that will respond very deeply just by introducing PD-1 blockade. Now, this isn't enough in the rest of the patients. There is where the whole sort of Holy Grail of cancer immunotherapy lies today: is to identify the right sequence of drugs and the right combinations that would lead to deeper responses in the rest of the patients. And that is a very complicated matter. There are multiple multiple drugs that have been tested and discarded, have been tested and were successful and moved on to more advanced clinical trials. Some of them have made it to approval and so combinations now are available for many patients. But again, these combinations, usually in two immunotherapy drugs or immunotherapy and anti angiogenesis therapy, or immunotherapy and traditional chemotherapy have now advanced in the clinic and produce important responses. Of course, it's not good for all the patients, and half of these patients that are treated, or more, remain behind. So we need to rescue those. The idea is, now that T cell therapy can come in and be transformative in that space, hopefully.

Alex Jani, X-Health.show: 16:54

It works already in blood cancers.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 16:57

Yes.

Alex Jani, X-Health.show: 16:58

What what's the challenge – because there is a huge challenge with the solid tumors.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 17:03

In blood cancers, what was advanced very successfully is the so called CAR T or Chimeric Antigen Receptor T cells. And this was a brilliant actually. The idea that, again, started over 30 years ago. The idea was to have the T cell recognize a tumor cell not through its normal receptor, which is the T cell receptor, but through a synthetic receptor, the receptor that we can artificially create molecularly, which borrows the recognizing domain of an antibody. You basically engraft this antibody to a molecule that functions as a receptor, and on the inside of the cell has signaling domains that you borrow from the natural T cell receptors. Because it borrowed not only the signaling domains of the T cell receptor but also of costimulatory receptors and put them together in sequence, something that obviously, if you look at it, you say this will never work, but it did. And that was the extraordinary disruption that this CAR T brought to the field. Now, this works very well in cancer. Why? Because in cancers, we have surface targets on the cancer cell that can be very well targeted. These are shared with normal blood cells. But if you lose those normal blood cells, you can still live a normal life. And that's the trick. We eliminate the cancer, we eliminate a subset of normal blood cells but the patient is managed fine and can have a normal life, and many of these patients are cured. The problem starts with solid tumors because the availability of the surface targets is very low. We don't have today, and it will take at least a decade or two to start through very smart screens to identify targets on the tumor cell that are specific for the tumor. If they are shared with the original organ, then you create prohibitive toxicity. Managing a liver cancer and creating a liver toxicity... you can't live with that. That's the problem. Now we need to find alternatives that can target the tumor specifically without affecting the normal organ of origin or other organs. That's one of the big challenges in solid tumors. The second big challenge in solid tumors is, because these tumors are solid they're in an organ, they have a big component of the stroma. They're basically normal cells that have been taken by the tumor in the way of developing as an organ or as a mass. And these cells are programmed to support the tumor, not the immune system, so they become profoundly immunosuppressive. So when you send in a CAR T or any T cell into that tumor, it's very likely that even if it could recognize the tumor specifically, it will fail eventually. And so you don't lead to real important responses. These are the two key challenges we're facing today. There are, of course, other technical challenges but these, conceptually, are the two main barriers to provide successful therapy to patients. And we can talk about how we are addressing them.

Alex Jani, X-Health.show: 20:46

Right. This is what I want to ask next, because you just said about huge challenges and you also started with a very challenging cancer type, ovarian cancer. It this is a very, well, stubborn cancer, very persistent cancer. So could you tell maybe now about the most recently published paper, and the studies you did.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 21:13

Given how complex and challenging it is to develop the therapies, we have elected to not start from ovarian cancer in the clinic. We indeed are learning our steps in tumor types that are more permissive to immunotherapy. What are they? Melanoma, lung cancer, and other types that are more immunogenic than ovarian cancer, but we clearly do this in patients who have failed available therapy. These are already difficult patients – an easier tumor to work with but more difficult patients. We hope that the lessons we learn there eventually will lead us down the line to a successful therapy to ovarian cancer. But we're not there yet at the moment. What we have done is, we took the conceptual barriers to immunotherapy, one by one, and dissected out to say, how can we provide them important solutions to that. We inspired our work from the TIL therapy that Steve Rosenberg had developed and others have replicated. So we started there and we benchmarked our activities exactly with this kind of approach to say, OK, let's prove we can do it. If we can interrogate it very deeply to understand why it works in some patients, why doesn't in others, and what lessons can one draw in order to go to the next generation of therapy to make it better, and rationally build solutions that will then work also for other tumors. This is where the program is today. And, you know, you talked about this patient who responded. We had several of these patients. We either had a profound and ultimately complete response, and we hope cure, or sufficiently profound but partial response that was persistent for several months, up to a year, and then the patient progressed. This is our laboratory to try to understand what exactly goes right and what exactly goes wrong in these patients. This is an extraordinarily complex investigation, because you have the patient in front of you, you have to obtain samples and you have to do that in a clinical context. But the lessons learned out of these are extraordinary, because really, at the end it is where the truth lies. The work that we do preclinically can look really brilliant but at the end the truth lies in the

clinic: 23:49

Can you make this happen in a patient and in many patients? So what we've learned is that the first principle of

delivering effective therapies: 23:59

you have to give a high bulk of cells, sufficient number of cells that recognize the tumor. Now, what do these cells recognize? It's a very intriguing question. And in fact, the answer is that we don't know. So in the TIL therapy it's a sort of a black box at the moment. We know that in patients whom we delivered successful therapy, there were anywhere from hundreds to several hundreds of T cells that individually recognized a tumor antigen and had the specific T cell receptor sequence. There were hundreds of the sequences together. Each of these clones, we call it, represented by thousands, if not millions, if not billions of cells in the final product – they all recognize the same thing, but we don't know what. We are interrogating this deeply now to try to say, with the knowledge that we have on the antigens, where we can point a finger, what part of the product recognizes that versus other. But the majority of these T cell receptors or T cell clones are what we call orphan or unidentified. Yet we know that critically important to eliminate the tumor. That's the very interesting part of this therapy because you unleash a power of a natural immune response with hundreds of different clones that attack all sorts of things in the tumor. Which is why if you have a complete response, very rarely you have an escape. Very rarely the tumor runs out because you have so many paths of attack, so many different antigens, that the tumor doesn't have the time to elaborate the solution genetically and escape it.

Alex Jani, X-Health.show: 25:52

This is basically an army sent against the tumor...

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 25:56

Absolutely.

Alex Jani, X-Health.show: 25:56

...and the T cells are the soldiers.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 25:58

Exactly. And if you'd like – the tumor microenvironment is the battlefield. One, it helps very, very much to think that way because indeed, the T cells to kill, they need physical contact. They need to grasp on the target cell and break its membrane to inject into the cell substances that will induce death. So it's a one on one battle, and one at a time. The secret of creating a good army is that they have to persist in the host, in the patient. They have to find the tumor and get in, and then they have to be able to kill serially. We call them the serial killers – in a very bizarre way. They need to be able to kill, each of the cells at least a thousand tumor cells. To do that imagine a soldier in the battlefield, you have to be super trained and super adept cell, of course, and that's the aim.

Alex Jani, X-Health.show: 27:01

What does that look like in the melanoma patients? Let's go back to these melanoma patients when they stayed at the hospital, I can imagine for a couple of months or three months. How did you see this works, the therapy Could you mention a few of them? works?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 27:17

The patient will typically come in for the screening first and we'll do a series of tests. We'll have to do a small surgery to recover some of the tumor in order for us to grow the cells out, or biopsies. The patient has to fit a long list of criteria to make sure that we don't put the patient in danger by giving him this therapy. You have to have a healthy heart, a healthy kidney, a healthy lung, or reasonably healthy – all of the above. You cannot put a patient who has heart failure or kidney failure or a severely diseased lung because this patient has no margin for tolerating the harsh condition of the high dose chemotherapy or the the treatment that we give after infusing the T cells. We need to be able for this patient to tolerate a little bit of this one to two weeks of stressful condition. And if the patient fulfills many of these criteria, then of course the patient comes in, we grow the cells in the laboratory, and then the patient is admitted to the hospital. We give chemotherapy for five days, which for the moment is inpatient, and then the following Monday we infuse the cells. Then we give a sort of a backup cytokine. This is basically a drug that supports the growth of the T cells in the patient and it's called Interleukin 2. That is also hard to tolerate. And because it creates side effects, particularly it creates what we call capillary leak syndrome, so it activates the blood vessels, and they leak water, you basically get what we call edema. Your hands and feet, and legs will swell up. Your lungs can swell up with a little bit of water. One has to have a very good clinical team to follow the patient carefully, so you can give this drug at sufficient doses to support the cells but not to make the patient sick. That's the sort of the clinical skill to make sure that you accompany the patient up to a point that the patient can tolerate that but not beyond.

Alex Jani, X-Health.show: 29:44

And also, I'm thinking, psychologically, because then the patients at the hospital realize, they feel actually worse. So what did you do?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 29:53

This is the whole job of the medical and the nursing team to really support the patient through this and the we have a wonderful team. They are really extraordinarily compassionate. I think humanity in addition to the technical clinical skill is extraordinarily important there because the patient does need to be supported emotionally. From each infusion of this cytokine, Interleukin 2 to the next the patient needs to be a participant in the decision: do we go for the next or not?

Alex Jani, X-Health.show: 30:31

Can you take more?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 30:31

Yes. Can you take more do you want more? This is how you could feel, etc. Empowering the patient to be part of those decisions I think plays a very big role in them, basically, withstanding this. But clearly, it requires a lot of effort on the patient and on the team. That's a very important part of the job. In fact, we have developed a collaboration with the nursing team to really study for the first time – this has never been reported – making a patient-reported outcomes. What is the patient's experience through all this? And what can we learn from that experience to get better as a team, and to improve the therapy as a whole?

Alex Jani, X-Health.show: 31:12

Oh, this is awesome. So why the ovarian cancer is even more challenging?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 31:20

Ovarian, colon, gastrointestinal cancers in general, some of the breast cancers and so forth, are difficult or challenging. Why is that? There are two key reasons for that. The first is that the absolute number or the what we call the frequency, so the percent of T cells in the tumor that recognize more antigen is relatively lower than in other tumors that are more immunogenic. For example, let's say lung cancer in a smoker. In that condition you have hundreds of mutations that the tumor has acquired because of the smoking, because the smoking creates DNA damage and so these tumor cells are crazy. This creates a lot of opportunities for antigens that the T cells recognize and there are all sorts of other antigens that we don't know today. It is just the tip of the iceberg what

we know. These tumors: 32:25

melanoma, lung cancer, bladder cancer, head and neck cancer, and a subset of gastrointestinal cancers that we call MSI-high, that are genetically unstable, are the top of the list of immunogenicity. And these are easy targets for T cell therapy because you have a lot of cells to work with. You're going out to the next level, and we're talking about ovarian, and gastrointestinal cancers, pancreatic, esophageal, liver, colon – and the majority of these patients, unless they have a specific mutation, or they're virally induced, the majority of these patients are on the low side of antigenic load. So that's one problem.

Alex Jani, X-Health.show: 33:08

So it's difficult to harvest these T cells.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 33:11

No, we can harvest them, there's no What you mentioned here is that for the lung cancer, smoking is problem but among the T cells that you harvest, let's say 95% of them are non-tumor specific. They're just inflammatory cells and you need to go find the tumor-specific in order to get those out. If you grow everything out, the potency of the product is going to be very low because the relevant cells have a very low frequency, very low percent of that product. So that's one of the main problems. The second main problem is that the microenvironment of these tumors is highly immunosuppressive. It has to do perhaps with, from the evolutionary standpoint, the abdomen in general is a domain of the body that does not like to have an immune response, does not like to have inflammation. There are a lot of anti inflammatory mechanisms that slow inflammation down and these the tumor co-ops and creates an environment where the same mechanisms that are naturally running in that environment. And therefore, T cell therapy becomes more problematic. The same, obviously, the barrier is for the immuno-oncology drugs, so PD-1, CTLA-4, and so forth. TIL therapy has the same challenges. This is where we need to now become better and smarter. a risk factor, like what do we have in ovarian cancer? Smoking aside, what risks do we have? One of the most important risks is actually genetic. It is And the prognosis. What's the prognosis for the patients with particularly clearly demonstrated for patients who have BRCA-1 or BRCA-2 deficiency and this is inherited from one of the two parents. Having only one of the two chromosomes with that allele, with that mutation, is sufficient to create a lifetime risk that is very high for breast and ovarian cancer. the current gold standard of treating ovarian cancer? Breast more ovarian less but nevertheless we were talking about up to 30-40% of lifetime risk for a patient to have ovarian cancer if one carries BRCA-1 mutation, for example. But there are also more subtle mutations and non-genetic alterations that lead to the same type of phenotype. And of course, there are other risk factors such as reproductive function. The oral contraceptive reduces the risk for ovarian cancer, breastfeeding also. Tubal ligation, also. So there are some mitigating factors and the truth of the matter is we don't quite understand if there are other environmental exposure risk factors. They haven't been identified to date. So we have, as a field, I think we have made a lot of progress in terms of keeping the patients alive.

Alex Jani, X-Health.show: 36:42

I'm asking because when you google it, it is five years.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 36:45

It's true, particularly, with the PARP inhibitors. What we have done today is keeping the patient disease-free for a longer time. But this, paradoxically, hasn't really impacted the overall survival of the patient, so the five year survival remains still very long. The majority, the vast majority of the patients with advanced ovarian, actually end up succumbing to the disease. We can't save these patients to date but hopefully we will in the in the near future. We'll see. We'll see. Could you tell us a bit more about this published paper and the studies in 17 patients that you did? What were the criteria for them to be admitted? And what was the therapy? As I mentioned before, we started our program with the sort of traditional details that we learned from colleagues in the US, MD Anderson and National Cancer Institute. We basically reproduced the international results with one important difference that most of the results internationally have been produced in advanced melanoma patients in the pre-PD-1 era. There was a big question whether after PD-1 failure, TIL would work the same. This question was answered by three studies. One is a single-arm study that was run by biotech in this patient population that reported about 30+ percent of response rate. Another randomized study was run by the Netherlands Cancer Institute in collaboration with Copenhagen's Herlev Hospital. This was a randomized study, where they reported a 50% response rate in these patients but they were treated earlier. It was a second line and randomized against Ipilimumab. And then smaller studies, including ours, where we saw that in patients who had failed PD-1 or CTLA-4, even in very advanced age, we can get an important response rate. We reported a 46% response rate in this patient population, in 13 patients. Now, with the lessons we learned out of that study, one thing became very clear, that the absolute number of tumor specific cells, and their frequency in the product is critically important for success. It became important to really expand tumor specific cells as much as we could. So we developed a second generation T cell therapy, what we call the neoTIL. This was an attempt to enhance within the product, or enrich within the product, cells or clones that recognize tumor-specific neoantigens. What are the neoantigens? They are basically, peptides, that the T cells always recognize, they're short peptides. But these peptides carry in them, somewhere, a mutation. That is the mutation that are part of the mutated landscape of cancers. Some of these mutations translate down to proteins and peptides, and these are presented on the surface of the tumor cell. That's what the immune cell patrol for and the T cells patrol for this and find them, and get activated, and attack. So we reasoned that by enriching the product for these particular cells that recognize neoantigens, we could expand the opportunity for TIL in melanoma and other patients. So we treated, as you said, 17 patients with melanoma, lung cancer, and other tumor types. And this is an ongoing study that we're still analyzing. But in the context of that study we have seen some important responses and we're learning what really drove those responses. So this is an ongoing work, has not been communicated yet. But it's an important work, it's basically the second stage of our TIL therapy development. And next we go to even better cells.

Alex Jani, X-Health.show: 41:04

You mentioned advanced stage, could you define this advanced stage? What stage it is?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: These are typically patients who come to us that are multi-metastatic. Their diagnosis has been stage 3 or 4. They were not resectable in terms of upfront therapy, they received the standard of care therapies in melanoma these days, which is IPI NIVO, or it can be just Pembrolizumab for other centers. And then other therapies in lung cancer: 41:10

chemotherapy with radiation or with immunotherapy, and all sorts of accepted approved combinations for therapy. We receive these patients after this therapy, or at least one line of therapy has been exhausted, and knowing that the patient has really no possibility for cure, whatever other lines one would use, would be just palliative and not curative. And one has to really, of course, note that the earlier we introduce the TIL therapy, the better it is. Because the more therapies you give, particularly if they're chemo therapies, then you damage the T cells in the body and so you then cannot expect them to perform so well. It would be very important to move this potentially curative therapies earlier.

Alex Jani, X-Health.show: 42:53

What you use is, you were mentioning this TIL therapy, but also something new, you enhance these T cells with, what you call, the personalized dendritic cell vaccine. Could you tell us about that? What's that? And how does it support the T cells?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 43:11

So there are many ways to really bring help to the T cells in the way to allow them to overcome the tumor resistance, the tumor barriers. Conceptually, one could go into four domains. One is what you just mentioned, which is the dendritic cells. What do dendritic cells do? Or other types of vaccines, could be an RNA vaccine, as long as is a potent vaccine. These, basically, support the T cells. You can use that vaccine either before you harvest the tumor, with the hope that this will enrich the quality of the TILs you harvest. Or, and/or you could use it after you transfer the T cells in order to support these T cells and provide them with additional help. And that, in preclinical models, is working. There's something that we should be aiming to do in the clinic. For example, this paradigm is being used also for CAR T. The idea is to provide a CAR T for the patient and then a vaccination against that specific antigen, which is very interesting idea. In early clinical studies, this looks like it's increasing the potency of the cell. A second conceptual idea is to provide combinations after the T cell therapy. We administer the cells and then we need to identify drugs that might be helpful for the T cells to function better. These drugs typically would go and target tumor microenvironment pathways that would prevent the T cells from working. The problem here is that many tumors are different. And you would need a combination of drugs, which is very difficult to implement clinically, to give the cells and then give a two or three additional drugs to the patient. Because for one, you could also create a lot of toxicity by combining multiple systemic drugs. A third approach is you reprogram the cells in vitro. So during the expansion, you make the cells better. And there's a lot of work ongoing now to try to do that. And to some extent, we can do it, to reprogram the cells and make them younger and more powerful. And then ultimately, something that in an area that we work a lot, is to re-engineer the cells genetically, so that they can themselves produce factors that when they go into the microenvironment, will be released. Then the cell becomes sort of a micro factory that will release drugs in the microenvironment, and the drugs that you would need for the cells to work better. So that's an area of very intense development. We're talking here about clinical studies. So these treatments are not widely available, right? How do you see the availability of them to a wider population of patients? That's a very, very good question. This field, unfortunately, although it appears to be developing rather rapidly, it also develops slowly at the same time. Because clearly, there are very important regulatory constraints. It means that we have to make sure that all these products are of very high quality. And the pace of development, obviously, can be reasonably slow, because every patient needs to be treated at the time and you cannot test so many ideas at the time. So one idea at a time. Nevertheless, I think that the regulatory environment could evolve to accelerate this testing. One of the opportunities that we have now is with this sort of hospital exemption mechanism that is being developed and discussed at the national level, it was already approved in Europe. And there, it's already demonstrated that they can largely accelerate the development and access of patients to these therapies. I'll give you two examples. Or three even. In Germany, this hospital exemption mechanism is used by university hospitals, and in Italy to accelerate clinical experience with new therapies. To the benefit of the patients and to the benefit of science because the more of these we do, the more we learn This is why, what I read in this paper about the ovarian cancer, how to do it better. But at the same time patients benefit because the likelihood of the therapies to succeed is quite high because they are very carefully and rationally developed. So if you look at success rates in this phase 1 clinical studies, you can have from 30 to 50%, or even more responses. you didn't use the placebo group, right? You refer to the study that we did one when I was at Penn and we published two studies consecutively. The first was the dendritic cell vaccine study and then the adoptive T cell therapy. That's correct. So in a typical phase 1 or a pilot study, you don't have to randomize. And as long as you do it carefully and with the support of the regulators, then you just basically treat all the patients and it can be, depending on the technology you're introducing, if it's a completely new technology, you have to do a dose escalation. So start a little lower and then go to a full dose that you think might work. It's a lot of guess work there to say what would be the minimum, biologically active dose. Phase 1 basically aims at piloting this to say, Okay, is it safe and can it be done? And then you collect also clinical data, efficacy data as a side knowledge, we call them secondary endpoints. Then if that is convincing, you go to phase 2, which is a larger number of patients still doesn't need to be randomized. And some regulatory agencies feel comfortable providing approval, even in the absence of a randomized study, as long as the study was well designed with a single arm, and proving the benefit in a population that historically we know has very little to gain from standard of care – existing therapies. And then, of course, you go to the phase 3, which is randomized study, against standard of care for approval. But indeed, in the early stages of development, you don't need to randomize. And I think this is the potential opportunity for the patients, because in many of these studies, the success rate, as I said before, is quite high. Entering a phase 1 study for a patient means that there is a chance for a benefit.

Alex Jani, X-Health.show: 50:21

How can they enter that? I've just gone across several discussions on how hard it is actually to find the clinical trial that the patient fits the criteria, the criteria actually fit the patient needs. There needs to be this match. There isn't really a European good database to look for that.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 50:48

You're right. So Europe, I think, runs behind the US in terms of support for clinical studies. In many ways, one of them is what you just mentioned, which is basically a tool that allows patients to find the appropriate study or doctors. The only tool that we use today is the NCI, the National Cancer Institute in the US, which has a global mission, they have assumed a global mission. And that, allow me to say, we owe the US taxpayers. But it's a global benefit because any studies from China, Korea, Japan, Europe, etc, are registered, or are expected to be registered, the moment they open. We typically do that. There is a very good search engine and you can find really the type of study that could be good for any particular patient, for particular types of disease and biomarkers driven and so forth. The second part where we fall behind in the European continent, is government support for clinical trial cooperative groups. So in the US, there is a very important part of the budget of the National Cancer Institute that is distributed to cooperative groups and allows them to have the necessary infrastructure to run these kinds of studies. In Europe that doesn't exist. So I think this is a very important gap that we have to fill.

Alex Jani, X-Health.show: 52:18

You know, I'm just looking at the question, you know, I've written down here, what keeps you motivated in your job? I think I can sense that. And I think the audience can sense that too. But is there anything that actually hesitated? Were there times of hesitation? Would you continue. Or were there these dark moments in your career? Because you're developing new solutions for patients.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 52:52

I would say that it would be non human to say that there are no dark moments. Because, obviously, I think that everyone in this space, who is motivated to develop new therapies has to have a very strong dedication. I would like to quote here, Rita Levi-Montalcini, who was a Nobel Prize winner, an Italian scientist, a woman, who survived the Nazi persecution and then made it all the way to win a Nobel Prize. Her research was in Italy and she gave an interview and said that they ask her what's the secret for the success, and what would be the advice to the new generations. She said, I would characterize it as an unjustified optimism. And I think this is what really drives most of us in this space, because you're exploring and the barriers are constant, and the difficulties are constant. They can be driven by biology because you just don't understand why this is not working. They can be driven by funding because you don't have enough money to go the next step. They can be, very unfortunate, driven by politics because someone out there doesn't think that you should be doing this against the benefit of the patients or an institution. And it can be by all sorts of operational complexities. I think operations are so critically important in setting up in an environment that really goes all the way from an idea to treating patients and learning from these patients back what we call reverse translation. But you know, what is very clear is that we believe, myself and many others who are in a similar situation, we believe that there is a solution down the line and that solution will provide clear benefit to patients. For me where the motivation comes from is when I was in the US I spent 20 years as a clinician. 15 of these years I practiced gynecologic oncology and I very much enjoyed the clinical practice and the surgical practice. It was a great satisfaction when you had a patient with very complex abdomen due to ovarian cancer and at the end of the surgery, and we're talking several hours of surgery, you basically cleaned up everything and this patient is now site reduced at 99%, given her a new prospect for a few years of life. But it's equally disappointing when you see the same patient coming back with a relapse and eventually die. I think that's what provided me really the motivation. Relentless to be able to break through all these barriers I mentioned before because patients are waiting for solutions. And we owe it to them to basically dedicate our lives to the solutions. The difficulties of every day be, that funding, politics, operations, or biological difficulties or complexities in trying to decipher a mechanism and finding a solution for it, should not stand in the way. And we should carry on. And because we owe it to them.

Alex Jani, X-Health.show: 56:16

What do you need to make it happen?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 56:21

I think this field will greatly benefit from enabling conditions that will accelerate it. What would be the first barrier is the very high bar posed by the regulatory constraints. European medicinal agency or the EMA and Swissmedic pose a very high bar in academic endeavors that enter the clinic is a phase 1 study, they are basically at the same level as production of cell therapies or gene and cell therapies by pharma, at the stage where an approval has already been granted and revenue is expected. What we face in Europe, unlike our US colleagues, let alone our Chinese colleagues, I will get to that in a moment, we face a very high bar for entering into the clinic and running a phase 1 clinical study. This means a lot of expenses and time consumed in regulatory reviews. That is a break. That's a decelerator. What we would need is a careful revision of these requirements in order to let us do the job as safely as we're doing it today but by somehow reducing the economic burden. I'll give you an example. When we produce a cell in culture, all the raw materials that we have to bring to that cell culture has to be qualified as GMP. And that brings a price tag of let's say, five to 10 fold above a research grade material. Now, our US colleagues are allowed to use research grade material, in a phase 1 study provided that material is carefully documented and safe. So in their hands, a phase 1 study would cost less, and also be done more quickly. Because if we need a new ingredient, to produce a cell, which is not available, today we have to commission it to a specific chemical company or a protein manufacturing company, in GMP quality, which will take two years to be delivered and hundreds of thousands of francs or dollars to be paid.

Alex Jani, X-Health.show: 58:49

It sounds impossible in personalized care.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 58:52

Well, this, this is the reality. And so that is sort of a break to the development. If we could go faster on that, of course, that would be extremely helpful. The second barrier is the financial barrier. Clinical studies cost a lot of money. Therefore, what we need to find is ways to subsidize them ways to provide financial support. There are two potential solutions to that. One is that philanthropy moves in. In the US, this works exceptionally well, perhaps because of the tax breaks. There are incentives for visionary people with means to provide support to academic institutions. And indeed, every academic institution in the US, large institutions bring in hundreds of millions of dollars per year to support their mission. And it's understood by everyone that the government funding is not sufficient. Although present, it is not sufficient to bring an institution to its highest levels of performance. Philanthropy money, in fact, is a catalyzer. Big cancer centers in the US, for example, bringing 100 million to $500 million a year to support work. That money is spent in clinical trials, in infrastructure, nurses, doctors, research. Here we miss that. Switzerland has no tradition in doing so. So that will be extraordinarily helpful. The second area, where we would strongly accelerate and catalyze is a rapid approval of reimbursement mechanisms for these innovative therapies earlier than at the end of the line, when an approval is granted for market authorization. One has to think about innovative ways such that academic clinical studies can be supported wholly or partly by insurance reimbursement or a reimbursement mechanism while a study is ongoing. The legislative framework for that potentially exists but it's not commonplace to apply it. I think the legislative framework has to create explicitly these conditions such that we can really take advantage of them. Now the so called hospital exemption is a window of opportunity, I mentioned earlier. Spain and the Netherlands, what these colleagues actually managed to do is to produce academic T cells in the context of the hospital exemption and get it approved for patients. Now in Spain patients can receive CAR Ts produced by an academic hospital in Barcelona. And, you know, this doesn't compete, in fact, with commercial CAR Ts from industry because their focus is on disease areas where industry doesn't supply CAR Ts. You create an ecosystem where the patient gains and at the same time, there is a rapid advancement of these technologies. Of course, academic institutions and research programs gain a great deal by developing the experience and all of the observations around these patients. In the Netherlands, colleagues got TIL for melanoma approved. Now patients with melanoma in the Netherlands and in Denmark, have access to these TILs with reimbursement by the government.

Alex Jani, X-Health.show: 1:02:45

Sounds like a path to follow by other governments.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:02:49

I would think so, yes. And lastly, if we would create an ecosystem where late stage clinical trials would be reimbursable that then leaves a gap in the early stage clinical trials. I mentioned philanthropy as a way to accelerate discovery and early development. But the early clinical trials remain an orphan area in Switzerland. In other countries, particularly in the US, there are government funds that specifically support clinical trials, this is a completely different caliber of expenditures than the traditional science grants. The science grants, with 200-300,000 dollars or francs per year, there is sufficient money to do the work and advance the program. In clinical trials, you have to add at least one or two zeros to be able to basically conduct a phase 1 clinical study. In cell and gene therapy we're talking about 5 million – a clinical study from the beginning to the end. So this mechanism of funding doesn't exist in Switzerland. That obviously leaves very talented academic groups that would have the potential to bring something to the patients and to the world, non supported.

Alex Jani, X-Health.show: 1:04:12

I hope the government officials, they listened to us now. Now still sticking to this gloomy picture, the future of cancer incidence doesn't look good, does it? There will be more cancer incidence in a world population, this is what you said at BioAlps event.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:04:34

It's a unfortunate truth that we need to put our hands and minds around because all the epidemiologists are forecasting, basically, a doubling of the cancer patient population within 20 years. This has never happened, unless there is a pandemic of some sort, in the medical environment. Imagine that over the next 20 years hospitals and health care's have to double all of the infrastructure that provides care to cancer patients. This is an extraordinary task and we will have to do it. I don't think there is a way out of it because patients will continue to come. Now why is that? Epidemiologists again, interpret that in two ways. One is that there will be approximately 50% increase in new cancer diagnoses. This is because the whole population is aging. The age pyramid is now inverted. There will be a lot more citizens over the age of 50 or 60 than young citizens in any Western country. Whereas if you look at developing countries, the majority of the citizens are below 30. So this has profound implications because the risk of cancer increases after the age of 50 exponentially, and particularly after the age of 70. That will produce really the increase of cancer incidence. And the other is that because we have non curative therapies today that come in several lines for any particular disease, we keep patients, luckily, which is, which is wonderful, alive longer but they continue to be patients. They will come back on a weekly basis every three weeks, two weeks for their treatment, their imaging and their laboratories. Often for complications from the treatments or from the disease. That generates an enormous burden, obviously. That accounts for the other 50% of the increase. So we need curative therapies and we need preventive strategies. Governments need to start working today to really implement the aggressive prevention campaigns, information campaigns, prevention strategies. Luckily, vaccines are coming up. They show important promise that can be applied in early areas of cancer, sort of the natural history of patients. And immunotherapy, particular T cell therapy – I view personally as one of the obvious potentially curative therapies. I think investments have to go there to basically fund this because T cell therapy, unlike any other therapies, unlike also drug-based immunotherapies, are a one off. So if we can make this effective, not complicated, and not producing important side effects that will require the patient to stay in the hospital for months, and we can get the patient in and out quickly, with an important response – that patient is out of the system for good. This is what I think is going to be making a difference down the line. But we need to accelerate development.

Alex Jani, X-Health.show: 1:07:42

The investment is higher in these T cells but, I mean, this is human life at stake, so I mean, we shouldn't really count how much do we put in there.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:07:56

Well, unfortunately, there is not sufficient investment from governments. Recently, we made the calculation of what's the national investment by federal agencies in various countries. For example, in the US, I believe this to be right, there was estimated to be about $20 per citizen per year in cancer research...

Alex Jani, X-Health.show: 1:08:21

Oh, wow. A lot lower than 20 bucks?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:08:21

..which you think is nothing, considering the incredible economic burden that cancer produces today and will exponentially produce over the next 20 years. What we do know is that when money comes in for research, the mortality of cancer goes down. That is proven and has been proven very clearly by statistics in large disease domains, like breast cancer, prostate cancer, and other domains where the National Cancer Institute the US pumped in a lot of money for research. But in European countries in Switzerland, is a lot lower than that. Yes. So you can imagine the gap that we have today. I think this is a very important area for discussion.

Alex Jani, X-Health.show: 1:09:08

Where you see the chances are. The chances in terms of therapies, technology, something that's developing right now, to, well, actually, to find a cure? To, yeah, what do you want to achieve?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:09:25

I think, it's very clear that small gains are made daily and breakthroughs are coming every now and then. I'm very optimistic about how this field is advancing. We know a cure is feasible even for metastatic cancers. Look, 15 years ago this was not thinkable that an advanced metastatic patient could be cured of her or his disease. And today, we know that multiple immunotherapy approaches have demonstrated over and again the same principle that when successful – is curative. Complete response means cure in a significant number of patients. So we know it can be done. And now the question is, can we do better? Can we accelerate? Absolutely, we should. And where we, where I hope to sort of contribute, is a small piece of that, which means getting these T cells to work better, to be more efficacious.

Alex Jani, X-Health.show: 1:10:28

I was asking about technology or any developments now, in general, in tech that can support the new discoveries, the breakthroughs.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:10:41

Absolutely. If you think about why we were able today to develop this therapy is because of the convergence of different innovation areas, for example. The ability to introduce gene therapy, so the ability to introduce new genes effectively into cells, and integrate these genes into their genome without producing catastrophic damage into the receiving cell. Today, there are numerous technologies that are developed, and one largely tested, which is the lentiviral vectors, which appears to be safe, entirely safe in T cell therapy, and now increasingly shown to be safe in hematopoietic stem cells. This obviously opens the door for very important disease corrections. Think about blood disorders and so forth, even genetic metabolic disorders. That's one. The second is the cell culture methods to be able to expand the cells outside of the body and understanding how the cell behaves and what are their requisites for having a good cell at the end of that culture. And then, what today is largely enabling, is Artificial Intelligence. This is where we can really accelerate knowledge and understand what we should be going after. How should we make a synthetic cell? A synthetic cell, meaning an end product, the result of genetic engineering which behaves in a predictable but non natural way in the context of cancer. How can we make a T cell be a T cell in cancer, when cancer is trying to suppress it? And that is a synthetic cell because we have introduced now genes that can continue to support the function of that cell in spite of all the suppression that the tumor provides. There are lots of ways to do that today, it's a matter of testing. That's where Artificial Intelligence in my view is coming in to aid us in a major way. We can think of how we can make a computational modeling of how a cell works and what we should change? How microenvironment works and what are the cell networks? This is only able through Artificial Intelligence. Up to now we were one-at-a-time experimental evidence, which takes forever. Artificial Intelligence is going to explode the way this can be accelerated, like it does for drug discovery. The same will be soon, hopefully, for developing synthetic states and synthetic tumor microenvironment. I think this is a wide open area that will be largely transformative in terms of cancer therapy. And of course, all the technological advances in gene editing, genome editing, cell manufacturing, and automation. All of these will come to play a very important role in making the cell therapy affordable for the masses.

Alex Jani, X-Health.show: 1:13:57

This sounds like a bit "justified optimism", would you say?

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:14:03

Well, yes. We believe it, based on the current evidence and by looking at how the field is evolving, to be justified optimism. So unlike Rita Levi Montalcini, who lived in an era where technology was not as enabling and the obstacles from lack of knowledge, lack of technology, and lack of financial or political support were much higher than we face today, I think we are in an era of justified optimism. And I believe that this optimism will pay off.

Alex Jani, X-Health.show: 1:14:44

Thank you very much for this fascinating, really, and very important conversation, George. And I wish you, and humanity, really, many breakthroughs.

Prof. George Coukos, UNIL-CHUV, Ludwig Cancer Research: 1:14:57

Thank you very much.

Alex Jani, X-Health.show: 1:14:58

[POST-ROLL] I'm totally impressed by the audacity of researchers turned startup founders, doctors turned entrepreneurs or ordinary parents turned healthcare innovators. People battling the battles that no one fought before. For the eXtra health of the future. So if you see a startup posting on LinkedIn, show them some love, hit Like, comment, That's fabulous. If you have a couple drops more of that altruism, follow the X-Health.show, leave a review here. I'll be able to bring more of these visionaries to you. So a big thank you. You're awesome. See you next week.

SPEAKER: 1:15:31

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