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Clinical trials and advanced cancer care at NIH: Dr. Klemen

Doc Talks

Dr. Nicholas Klemen from NIH discusses clinical trials and advanced cancer care with Paltown Scientific Director Dr. Manju George. Recorded in May 2023.

Table of contents

0:00: Introduction to DocTalks
2:17: Dr. Klemen’s background/how did you become interested in colorectal cancer?
5:39: The heterogeneity of stage 4 colorectal cancer.
13:11: The process of getting a clinical trial referral.
16:59: Clinical Trials at the NIH.
26:40: How to find clinical trials at NIH.
34:17: The role of immune checkpoint blockade in treatment of metastatic melanoma.
37:25: Microsatellite instability in colorectal cancer.
40:17: An example of a patient’s response to TCR-T therapy.
46:28: Q & A

Manju George 0:00
Hello Everyone, welcome to DocTalks. I’m Dr. Manju George, the Scientific Director at Paltown Development Foundation, the nonprofit that supports Colontown. Today, we have Dr. Nicholas Klemen with us from the NIH. And he will tell us about, you know, what all is available at the NIH. Dr. Klemen, could you please start with telling us a little bit about yourself and how you got introduced to GI oncology?

Dr. Nicholas Klemen 0:20
Yeah, I actually, I got a couple of slides and maybe I’ll help. Let me go through a couple and then I’ll do that because I’ve got some things written. That’ll make it a little easier to follow. I just wanted to briefly see is this working okay. I have no financial disclosures. And my group has a collaborative agreement with a company called I Lovence which does TIL for melanoma. And, briefly, we’ve just also of course, always like to acknowledge the patient volunteers that drive our research, our referral research and apheresis nurse teams, the staff of the NCI Clinical Center, and of course, the US taxpayers in the US government, which funds the NIH, and all of our past and present colleagues. So yeah, I’ll talk about my background briefly and give some brief thoughts on clinical research and colorectal cancer in general. And then I’ll talk about clinical trials at the NIH and how to find them and specifically the trials that we’re doing. And so my background to answer your question. My background is in general surgery, and I did my research both in medical school and in residency, either at the surgery branch here at the NCI or I was a med student in Indiana and I worked in a lab of somebody who had been in the surgery branch . And back in those days, we were doing mostly melanoma. And I’ll talk a little bit more about that later. I did my clinical fellowship and complex general surgical oncology after completing my residency, and then I joined the surgery branch as staff in 2021. And so, you know, to answer the rest of your question, How did I get into gi oncology? Really, it was a couple of things. I mean, one, the surgical management of Gi tumors and particular colorectal cancer I found very interesting. But you know, as I think maybe a lot of people know we’ve had a lot of success in melanoma. And, you know, the sort of I don’t want to say the baton has been completely passed, but from our efforts here in the surgery branch, what we used to do in melanoma that is now being translated and commercialized by pharmaceutical companies, which is, you know, a great success story, you know, that’s what everybody’s hoping for. And so, you know, they’re sort of taking that baton now we do still take care of patients with melanoma, but that’s a lot less of what we used to do. And these days, the big challenge is all of you and people listening probably know already is that there hasn’t been success in colorectal cancer excluding Of course, you have the microsatellite instability- high folks who can have tremendous responses and benefit from checkpoint inhibitors. Success with immunotherapy in colorectal cancer, your run of the mill microsatellite, stable colon cancers has been a lot more temperate and so that’s what our focus now has shifted pretty much entirely in that direction, not only colorectal cancer, but you know, pancreas cancer, colon cancer cholangiocarcinoma, breast cancer tumors that aren’t really responding to checkpoints. So does that I can’t remember if you had any other questions, or if there’s anything else that you want me to cover before we keep going.

Manju George 3:54
I think that’s good. Thank you.

Dr. Nicholas Klemen 3:57
Okay, so I’ll just proceed then. And so like I said, I wanted to talk a little bit of, sort of, sort of big picture general stuff. And you know, I really think you should take everything you hear from me, but also anything you hear from anybody else with a grain of salt. When you’re talking about cancer, I mean, there is a textbook, but you can read the textbook but the truth isn’t really completely known. I think that’s an important point is that there’s only so much data out there and people analyze the data. And they have different biases and different perspectives. And you can interpret the same data multiple ways. And so a lot of doctors have different opinions about what should be done or what does this all mean and you know, what is the biology mean? Or what’s the best choice for treatment? And I think it’s just important to remember that the answer isn’t always known. And so you really and this is why I always harp on one of things I harp on is it’s always good to get a second third opinion, if you can, because you want different perspectives and different ideas. And so I’m going to share some of my sort of general thoughts about colorectal cancer. And this is just one doctor’s opinion. But that’s just sort of what I’ve come to from my years of training and reading and researching.

One of the first points I guess I wanted to make, because I think this is an important point about colorectal cancer that doesn’t get emphasized enough, but I think it really informs me why I’m interested in colorectal cancer and I think it’s really important for patients to understand this concept. So if we’re talking about stage four cancers, right, we’re talking about metastatic cancers here. I mean, we used to have these tumors called carcinoids or neuroendocrine tumors out and we still have them, of course, but um, they used to be sort of classified as just carcinoids. And there was just a ton of heterogeneity, meaning differences, and how patients would do. Some patients had really sort of slow growing disease, they might have a bunch of liver metastases and you repeat a scan and two years and they don’t look any different, right. And then other patients had really aggressive cancers and they could die from them pretty quickly sometimes. And what we’ve now done and in neuroendocrine tumors as we sort of reclassify them, because there is so much different heterogeneity, and we’ve come to realize that these are really almost different diseases in a lot of ways. I’m not gonna talk a lot about neuroendocrine tumors, but I’m making an analogy here. So for example, you can have a grade one neuroendocrine tumor and you can grade it based on how quickly it’s dividing and some other things where, you know, they tend to be pretty indolent, they tend to be slow growing, you do surgery a lot for these. But even if you do nothing for them, the patient will live potentially for years, sometimes even decades. Grade 2 neuroendocrine tumors a little bit more aggressive, you can still do aggressive locoregional therapies and that will provide cancer relief and symptom relief. A grade three neuroendocrine tumors start to get a lot more aggressive. You can still sort of manage them. There’s some overlap, but they tend to be a lot worse actors and more fast moving and then there are neuroendocrine carcinomas, which are almost more like pancreas cancers. And so you can see this heterogeneity now has been broken up and we have we now have sort of more discrete clinical entities. And when you’re talking about gastrointestinal tumors, so again, thinking in the stage four setting if I was going to think about pancreas cancer, you know, pancreas cancer tends to be, in Stage Four setting, it’s pretty, I don’t want to say it’s monolithic, but the management is pretty consistent. You’ve got the sort of standard systemic therapies that you go to. You do do metastasectomy you know, like a liver resection, for example, with a solitary pancreas cancer metastasis. I’ve done that. And it does make sense in very rare instances, but it’s not something that we routinely do because most pancreas cancers are so aggressive that it doesn’t make sense and it doesn’t help. Gastric cancer sort of the same story where it tends in the metastatic setting to be pretty aggressive. Now, there’s a lot of subtypes of gastric cancer, and this may be changing but and so the point I want to make is that I think there’s really a lot of heterogeneity in colorectal cancer. And we all sort of intuitively notice
I mean, some patients get surgery for their metastatic disease, other patients get hepatic artery infusion pumps, some patient you know, people are doing liver transplants, which may or may not be a great idea, but the point is, is you know, things are different in colorectal cancer. Some patients are getting different treatments than others and what you can see just with this simplistic graph is that there are some colorectal cancers that are really biologically a lot more indolent. And they may be amenable to certain treatment strategies and others, whereas some colorectal cancers almost behave more like pancreas cancers and that they’re so aggressive and so the reason this matters again, I’m just talking a very big picture here. And you can have dramatically different outcomes for the what I quote unquote same disease, right. You could do the same, you know, same metastatic presentation, you could do the same systemic therapies and one patient could live for less than a year and another patient could live for five years I’ve seen people with metastatic colon cancer, live for over 10 years or close to 10 years who didn’t get surgery, you get surgery and you’re cured with surgery. You can live for over 10 years, but generally if you if you’re unresectable you don’t live for 10 years, but I have seen people get close. So there’s a huge amount of heterogeneity.

And I think that’s important when you’re thinking about clinical trials. Because you know, I love the community, you know, Colontown has built and I think it’s extremely important sharing information and, you know, providing resources to each other. And I would just say though, the one thing to keep in mind when you’re talking about colorectal cancer and all the heterogeneity is that you really have to use caution when you interpret anecdotal results. Because if you think about a good outcome, like let’s say, you know, this patient had stable disease for eight months, six months, you know, that’s not unprecedented just from somebody who has, quote unquote, good biology. And similarly with bad outcomes, right, you can have bad outcome that may or may not be related to some investigational drug, it may be that patient had an aggressive tumor. So again, doesn’t mean you shouldn’t listen to what other people are saying and what their experience once it just means you’ve got to be cautious. And I think it also highlights the importance of tailored management and again, this is one of the reasons why I you know, I’ve gravitated towards colorectal cancer as a area of interest, because there’s so many different things that we do for colorectal cancer, for example, regional therapies for Stage Four disease I mentioned earlier, but we do surgery, ablation, we do hepatic arterial infusion pump, we do cyto reduction. Commonly we don’t do this for a lot of other cancers we do for some but not a lot of others. And so it’s really important to understand individual patients tumor biology, you don’t want to just say oh, stage four colon cancer. That’s the same as every other stage four colon cancer. No, no, you’ve got to really think about what is this patient’s disease telling you? How does it present, what does it look like? What is it doing? What are the genomic alterations, some of those can predict prognosis? And all of those things give you that perspective of you know, is this looking like a more slow growing tumor? Or is this looking more aggressive like closer to pancreas cancer and should I treat it differently? And so, again, these are important because if you don’t consider all of these things, if you don’t consider the individual, especially in this disease, I think there’s a lot of consequences from under treatment, and over treatment, right ,under treatment, meaning let’s say you have a medical oncologist who doesn’t understand that just because you have three liver metastases and they’re in an inconvenient spot doesn’t mean you can’t resect them. Right, overtreatment, an overly aggressive surgeon doing something that maybe doesn’t make a ton of sense biologically. So I think it’s important to get a multidisciplinary evaluation. It’s really important to get multiple opinions if you can do it. And then there’s heterogeneity. I guess the last one I would make since I’m talking about immunotherapy, but that’s that’s what I do. But there’s all sorts of interesting research questions that arise out of heterogeneity and why are different patients different and you know, when hypothesis is that maybe the immune system is partially responsible for heterogeneity that we’re seeing, and if that’s true, then you know, it really tells you that hey, maybe we’re on the right track and immune system can do a lot more than it already is.

So I wanted to also just give a few thoughts on clinical research. I’m sure you know, the other people have talked about the importance of this, but I would emphasize that it is really helpful to start looking early. If you’re interested potentially in clinical research. You know, it’s a slow process. I mean, getting from the time that you email and you get a referral to get a clinic appointment, you’ve got to go to whatever center you’re interested in. Talk to the oncologist. It’s a slow process, and I don’t think you want to you know, it’s not ideal to wait until your oncologist has sort of given you everything they can give you and the other thing to remember is that there are sort of diminishing returns to standard chemotherapy and accumulating toxicity. So the longer you wait, not only are you sort of you know, it becomes more challenging to get on a trial it gets it becomes more challenging to potentially to tolerate a trial. So I think it is beneficial to start looking early, and just putting your sort of ear to the ground and listening for what’s out there. And I guess I’d also make the point don’t assume that your doctor knows the best research options and to be honest, this isn’t a dig on your doctor. This is true for me, right? I mean I don’t know, you know, the research research in America. I mean, it’s very disjointed. I mean, I guess when I was a med student, I sort of assumed that everybody knew what everybody else was doing. But the reality is that you don’t and I don’t know what a lot of the other big institutions are doing at this moment. I mean, ASCO is going on soon. So we’ll find out but I do remember when I was here as a fellow when PD-1 therapy was becoming really a big deal for melanoma, but it was still in trials. I was speaking to oncologists who didn’t even know that it was a thing. I mean, this was a drug that was curing patients with melanoma left and right. And some of these oncologists who I would call them about their patient who we had seen and say, oh, you know, you should get on anti PD-1 and they wouldn’t have heard of it. And again, it’s not their job to know it. And the community oncologist has a lot to lot going on. So it’s not a mark against them if they don’t know what is investigational, but just the important point that, you know, your doctor may or may not know what the best research options is. And so it’s important for patients to sort of start looking into all that they can.

Another point I would make is that you know, if you do get a research consultation you know, you’ve got an existing treatment plant. I mean, you know, you can use that research consultation for a lot of, you know, getting new ideas on future trials or different trials or you can get ideas about well, how would you you know, what was your treatment algorithm look like? If you were me and our patients asking me sometimes what they think what I think about certain things, and I’ll tell them so. And the final point I would make, I would emphasize
is that there’s no contract right? You can sign a research consent, you do not have to go forward with research. You can withdraw your consent at any time. You do not need an explanation. So do never feel pressure and never feel boxed in. You can always withdraw consent, so don’t forget that part. All right. And so that’s sort of my brief, you know, sort of big picture thoughts that I thought would be worth sharing.

And now we’ll talk a little bit more about what we do here at the NIH and how I got actually initially I’ll talk a little bit about how it’s organized and how you can look into trials at the NIH. So this is actually it was kind of a challenging thing to sort of figure out how to think a lot about this, how to describe this, because I’m sure all of you are experiencing that the American medical system is not exactly the most efficient, efficiently organized system in the world. And so I was thinking about what are the differences between, you know, care when you would get it in an academic center care and community center versus care at the NIH in it? I think this is sort of one analogy I came to but when you go to a normal hospital, the mission is to provide comprehensive care, right? They have to take care of every patient. So if you imagine, of course with this marble analogy, right, these are the marbles falling down the different pathways. It’s not random, of course, but there has to be a spot for every marble that comes in, right. And then some people, you know, they get worked up and they get scans, maybe they get a colonoscopy, they end up you know, maybe they get surgery or they get oncology care or they get medical care. They go to the emergency room. But the point is, is that you’ve got to get you know, most hospitals have to provide comprehensive care from start to finish. Right, they have to do screening, they have to do your initial diagnosis, they have to provide the standard of care treatments. They have to be able to offer you know, second-line third-line therapy, and then sometimes they also have clinical research, although not always. But you can see that there’s already a lot going on. And so clinical research can’t be their entire focus. And so in many academic community centers, you just have to remember the extent of specialization is going to vary. The clinical trials may be limited and again, emphasizing earlier point providers don’t often know you know, what’s going on outside. at the NIH, really everything is clinical research. Now, we don’t it’s not that we don’t have any effort at screening, diagnosis and standard treatments, but there’s very limited effort for this and there’s not like it’s not certainly not high throughput. And everything that happens here has to happen on a clinical protocol. In fact, if you’re not on a clinical protocol, you can’t be treated here. If you’re on the NIH campus and you fall and hurt your knee and have to be taken to, you know, an emergency room actually, if you’re not an NIH patient, the ambulance will come to the NIH and take you somewhere else. You’d have to be on a protocol. And so NIH clinicians, you know, are usually hyper-specialized and they’re often leaders in the field or they certainly know people who are leaders in that field. So that’s one potential advantage of the NIH is maybe it’s not a great place for all facets of care, but it’s good in certain parts of the care.

And the NIH clinical trials can be more ambitious, just because there’s a lot of resources here on the NIH campus, although certainly there are lots of other ambitious and exciting trials going on elsewhere. But yeah, so and then there’s finally that, you know, there’s no organization or structure that funnels patients into NIH trials, like like there is in a lot of big health networks where you know, there’s like a main hospital and like different satellite hospitals feeding patients in and there’s sort of like this top-down approach. There really isn’t that at the NIH, it’s, it’s all just sort of entry-level.

And so I sort of just came up with this. So here’s a hypothetical example, you know, a hypothetical patient with colorectal cancer. I mean, the NIH really only fits in where there is a research interest in an active clinical protocol, right. So, you know, somebody with, let’s say, clinical symptoms of colon cancer, goes to a doctor. I mean, you know, the NIH really isn’t going to be your first place for that because there’s just not, not that I know if somebody here that’s interested in doing an initial evaluation, so you’re gonna get a colonoscopy, CT scans pathology, finally, let’s say so let’s say you’re diagnosed with stage three colon cancer. Now, there are some patients you know, we do there is in certain cancers, colon cancer being one of them. There’s other cancers that there is an interest in studying the primary tumors and so for that research interest we do, we do have the capability of doing a standard-of-care surgery at the NIH for patients who meet eligibility. But I don’t think that’s true for every tumor so I can’t get I couldn’t guarantee that every cancer there would be somebody that would be willing to just do a primary operation, but again, colorectal cancer, I know that I personally in our group can do that. But again, then let’s say you have stage three colon cancer, you need adjuvant chemotherapy, right. Let’s say you need FOLFOX in the adjuvant setting. I’m not sure there’s anybody here that would offer that right. So you would have to go to an outside oncologist to get that done, begin with radiotherapy. We do have radiation oncologists here and I’m just not sure if any of them have any particular interest in giving, let’s say you had a rectal cancer, you needed RT in addition to your surgery, I’m not sure there’s anybody here that could give it so we can help resolve these problems by coordinating with an outside oncologist or an outside radiation oncologist, but you can see how you know, we don’t do all the facets of care, right? We do certain facets of care. And so you go into remission because you have surgery in our team and let’s say the disease comes back. Again, you know a lot of clinical trials require that patients get the first at least one line of standard systemic therapy. So let’s say now you’re gonna get FOLFIRI for metastatic colon cancer. Again, there is you know, there are medical oncologists here but their ability to just give a standard treatment is very limited. Now again, some some people need surgery for metastatic disease and our group in the case of colon cancer group and others can offer that but for every tumor, that’s not necessarily the case. So there has to be an active research interest and an open protocol. And then it’s really after progression and patients that have progressed on first-line therapy that the NIH shines because now we have an opportunity to enroll patients on trials but again, I have an asterisk here, right because the asterisk is the patient has to be eligible and we have a lot of eligibility criteria. So so it’s not necessarily all comers will get will be able to get care here and that’s one of the challenges.

Manju George 20:17
Can I interrupt for a second? Is there a place where you have the list of trials at NIH that we can refer patients to? That very useful because, you know, then people could see for themselves where they fit in what you have to offer, right?

Dr. Nicholas Klemen 22:56
Yeah absolutely. And I think that’s maybe the next slide. So I’ll just briefly just say, you know, how the NIH is structured. And so the way it’s organized, right, it’s, again, it’s not really this top down thing. It’s, there’s just a lot of different branches. And these different branches, conduct trials, kind of independently from each other, and sometimes different branches can conduct trials for the same disease process. Which can be very confusing.

Dr. Nicholas Klemen 23:30
Yeah, and so I guess the final point, though, is I would emphasize that the NIH, the Center for Cancer Research, I mean it is a full service hospital, right. So it’s not that we can’t do all these other things. It’s that we don’t offer them as a routine standard of care unless there’s a protocol. So, you know, if patients have issues on our protocols, we can take care of them because we do have radiology, we have interventional radiologists, we have pathologist pharmacy, we have an ICU and so anything you need if you’re patient here we can provide it’s a small hospital, but it’s a full service. And so, yeah, so to your point about the good place to find a trial so the Clinical
Center website is a really useful resource. And that’s just ecr.cancer.gov. And that’s this big building here is the NIH Clinical Center. And so this website is useful so you can find so how do you find trials at the NIH clinical center, so you can go through clinical trials.gov That’s one option. And so people who search for trials on clinical trials.go You know, trials that we’re doing will be listed there, but if you are interested in the NIH in particular, one approach you can email the branches directly and you can also email investigators directly. So for example, you know, my boss, Steven Rosenberg, who has been a pioneer in cellular therapies, you know, I just show him, showing you here I just Google his name, Steve Rosenberg, clinical trials. And here you can see the first link that will take you to his profile on the CCR website that I just showed you. And you can see on the website, there will be a link to you know, the research nurses that run his team, there will be a link to his protocols. So that’s one way to do it. Another way you can do it is you can review different NIH branches. So this is just a screenshot of the website and this just shows, you know, the clinical branch directory. So we’ve got just the Center for immune oncology, and it shows the physicians there. There’s a developmental therapeutics branch. The surgery branch is listed. It’s farther down, but this is just the point that you can review the different branches at the NIH and say, I have bladder cancer, I can contact the general urinary malignancies branch. And then finally, another option is the CCR website does have a nice Search option. So you saw here I just went in and I just typed in colorectal on the CCR website under the trial search, and you can see so it’ll pop up different and these are just three studies again, just a screenshot so they’re more listed, but these are just the top three. You can see for example, the third study listed you know, this is the protocol by one of our colleagues in a different branch, Dr. Hernandez, who is a surgeon as well, in his study, this is a study of hepatic artery fusion pump, and he’s adding an additional agent to that so so this is a good resource as well. If you’re interested in looking for clinical trials at the NIH Clinical Center. So before I move on, any questions about the NIH organization, I realize it was sort of very vague and high level but it’s sort of a fuzzy, fuzzy thing sometimes to articulate.

Manju George 27:05
I think I, this was very good. And I you know, I have to say this that I especially loved your introduction, you know, talking about how heterogeneous CRC is because that’s something that we try to tell people that you know, just because someone had a certain outcome does not mean that you know, any patient can have the same outcome. There are a lot of factors involved. And it’s really nice to see that you have taken the time to present it like that. I think that that would be very useful for patients.

Dr. Nicholas Klemen 27:38
All right. And so I guess there’s some questions in the chat. Do me to wait until the end or do you want me to, we can kind of look at it now. Okay. So let’s see.

Manju George 27:50
Yeah, and then one question is, patients over the age of 70. Are they accepted in trials?

Dr. Nicholas Klemen 27:56
So it’s, I think it’s protocol specific. So our protocols so even though we’re the surgery branch, I think I sort of glossed over this but um, you know, our branch name is sort of a misnomer. I mean, what we do in our group the surgery branch, the name comes from our training, or background, we are all surgeons, but are we are not doing our trials aren’t really, you know, trials evaluating surgery, really we do surgery, but the point of the trial is not to test new ways to do surgery. What we do are set pretty much universally cell therapy not entirely on like solid cell therapy, but mostly cell therapy. And so for our particular trials, most of our age cutoff is in the ballpark of 71 or 72. And there are a lot of reasons for that but cell therapy as I’ll mention, because this is gonna be a pretty brief overview, but it’s, it really has a lot to do with the rigor of the treatment and so we focused on a younger population. Okay.

Manju George 28:59
And then the next question is: Can international patients go to NIH?

Dr. Nicholas Klemen 29:02
The answer is yes, but I don’t know all the specific rules. Because I know we’ve have had patients come like from Canada. We have had patients that are international, but I think there are certain rules about that and I to be perfectly honest, don’t know them.

Manju George 29:22
Okay, but that means that you know, there might be a place for someone to conduct an ask about those specifically, right?

Dr. Nicholas Klemen 29:28
Yeah, if you ask I think we’re very — I don’t know I’m very accessible. I feel like NIH docs are very accessible. We’re not like clinically, that’s one of the nice things about the NIH, I guess is, you know, we’re not it’s not a huge high volume Clinical Center. So I certainly don’t mind getting emails from patients and, you know, if you’re interested in the protocol, you can email the investigator that’s listed on that protocol, and ask them directly and that’s what I would do if I were you. And your emails are right there on the website. You know, if you follow, you know, the protocol information, you’ll see what you’ll see an email on there. So.

Manju George 30:04
Okay, I was thinking the next series of questions are more about trials. So I was thinking that maybe we can cover the clinical trials in the surgery branch and then go over the next set of questions.

Dr. Nicholas Klemen 30:14
Sure. Of course, okay. All right. So as I mentioned, I sort of got my start in melanoma and started doing research in melanoma in like 2008, actually, and back into that when I was a med student back in 2008. This is a randomized phase three trial evaluating two regimens of chemotherapy for metastatic melanoma. And the median survival back in 2008, was in a six to 12 months or so. We really melanoma was very similar to pancreas cancer and its outcomes back then. But these days, I would say we may never actually know. Again, what the median survival for metastatic melanoma is right because median survival is the time it takes for half the patients to have the event if you’re talking about overall survival, it would be dying but or progression-free survival, it’s disease progression, but in melanoma, I think these days we’re curing more than half of patients. So you can never hit a median again. So really, the and that a lot of most of it has been immune checkpoint blockade, as I’m sure of all you’ve heard. But there’s really been this revolution, I mean, therapy that it started in 2011. But really started a little bit before that. And when I think you know, just very high-level big picture and in this, this part of the talk is going to be sort of short and high-level big picture stuff. But really, when I think about immunotherapy right now proven immunotherapies there’s really these two approaches cellular therapy and immune checkpoint blockade. And cellular therapy, we can talk about car T tumor-infiltrating lymphocyte therapy and TCR T and I think for solid tumors, the ones that are highlighted in red are going to be the way to go. For liquid tumors car-T works really well. And so we focus here on TIL and TCR T. And the way TIL works I’m sure a lot of you have seen this graphic but the way TIL works is that you excise a tumor. Inside the tumor, there are tumor-infiltrating lymphocytes, that’s where we get the name of TIL and we basically take those T cells which in the tumor are outnumbered and sort of outgunned and tired. And you grow them in a laboratory and you give them all the growth factors they want all the media they want and they just really activate and the expand and they sort of shake off all of their anergy and their inhibition and they begin to proliferate and then we can choose the different cultures that have the most reactive T cells. And we can give those back to the patients after lympho depletion and so this was really these efforts was they were really led by the surgery branch using TIL for melanoma, and there’s been some really dramatic responses. So this is one patient who had all these liver metastases and got TIL treatment and 30 days and it’s a one time treatment, right? So you get your chemotherapy, you get your cells, the chemotherapy is given about for close to a week before the treatment to sort of deplete the existing immune system and make way for the new immune system we’re building. You give the T cells and then you give a little growth factor but it’s a one-time treatment. That’s it. And so this patient 30 days later has this nice response. And so we saw complete responses in about a quarter of patients with metastatic melanoma. What was most exciting is that these responses are durable. So this figure here shows overall survival. And if you look in the dark, dark, black line, you can see all patients, but if you look at the complete responders, I mean over 90% were alive, you know, 10 years later, they don’t their disease never comes back. So usually means the cancer is sterilized. And some of these patients who had a partial response also had a really long survival and actually a couple of these people too, and some of these were, you know, they had near complete responses. Maybe there was one or two sites that grew and we took it out surgically or a few of these people actually went off and got PD-1 and so it’s a little bit of a mixed bag. But this is really the result that that impresses us. And you know, now a lot of this was done in patients who hadn’t gotten checkpoint blockade and so then the big question is, well, you know, if patients get checkpoint blockade you do you take out all the people who can respond to immunotherapy and you’re left with ones that just won’t respond. And the answer is no, I mean, this was a randomized trial just published in the New England Journal comparing TIL therapy versus ipilimumab which is a checkpoint inhibitor in patients with melanoma that was refractory to initial checkpoint. blockade. And here you can see this is progression-free survival, a very significant difference in this randomized trial, and so the data for cell therapy has been so effective, it’s taken. It’s been a long time coming but it’s finally going to be approved. I think this year, I believe I don’t have any inside information of this but Iovance Biotherapeutics as a company doing this and I obviously have no disclosures or stocks or anything but the way that it works is that you can get your tumor removed at any hospital, your local community hospital and they will send your tumor overnight to a central processing facility. And they will culture the TILs and grow them and then they freeze them and they ship them back to your hospital and your doctor does you know the things that we do here right we give you the chemotherapy they give you their cells they give you IL-2. And the idea is that this is a good treatment option for patients whose disease did not respond or progressed after checkpoint inhibitors for melanoma. And so you know, it’s exciting I mean, so and I would say this as a surgeon I mean in the past surgery for melanoma was used similarly like it is in colorectal cancer in that you had melanoma and you had, you know, a solitary lung that or a solitary liver met. In years past it was certainly reasonable to go to the operating room and remove that because some patients you could cure them. But in the past you would take that tumor out and you would just throw it in a bucket of formalin and it would go to the pathology lab and that’s it. Some sometimes people will do research on the specimen but now those specimens, you know, I would argue they’re an invaluable patient resource right because if you have melanoma in it, if you’re having surgery for curative intent, if your melanoma doesn’t respond to PD-1 you’re gonna want those TILs and so in the future you may be in a place we may be in a place where you consider that specimen to be an invaluable resource that you want to save just in case.

Now, I mean, I’m sure as everybody here knows, you know, immune checkpoint blockade has been a game changer for highly mutated cancer. So you can see this figure what this shows is, on the x-axis where I’m showing this shows the mutation burden, the median mutation burden or given cancer and then on the y-axis, this is the response to PD-1 blockade and you can see this very linear correlation where you if you have more mutations, you respond better and here you can see up here in green is melanoma. And here in green is MMR deficient colorectal. They have a lot of mutations and they may respond nicely to PD one blockade, but all the way down here are 90% of colorectal cancers are thereabouts, who may have a lower mutational burden and really they respond less well than you would predict actually based on their mutational burden alone but nonetheless, they don’t respond to checkpoint blockade.

But what’s remarkable is even those microsatellite stable colon cancers, even the ones that don’t respond to checkpoint blockade, the T cells that can recognize the cancer, it can recognize the mutations in the cancer they are there so this is a study published a few years ago by our group where we we looked at neoantigen reactivities. And this is all manual testing. The science it would take me a while to explain but it’s sort of like the best way possible to test to prove whether a T cell can actually see the mutations in cancer. And you can see that, you know, we checked 51 patients with metastatic colorectal cancer, all MMR proficient, none of these were you know, microsatellite instability-high and 45 of those 51. We found T cells in at least one clone if you saw that could recognize the cancer. And that was true in most of these other cancers. I think pancreatic was a little lower than colorectal, but we could find those T cells and all the cancers. And so there’s this notion of cold tumors and hot tumors and colorectal cancer. Really, I wouldn’t say it’s a cold tumor, I would say maybe it becomes a cold tumor because we know early on there are even in MMR proficient colorectal cancers that seem to have an immune infiltrate and can respond to checkpoint inhibitors in the primary setting, but they just don’t in the metastatic setting. And so TIL therapy I think does have this potential to turn a cold tumor hot by the first week we can expand and enrich the cancer-specific T cells, right? So instead of the tumor being full of random T cells, maybe some of them recognize the cancer but maybe 90% of them recognize some random virus and they just happen to be in the tumor and they’re not contributing, right. They’re getting in the way. So by giving this chemotherapy, and expanding the correct T cells, we can really enrich for the ones that see cancer. We can also deplete immunosuppressive cells so T regulatory cells are myeloid-derived suppressor cells, cells like that, that can dampen down the immune response, giving the chemotherapy while the T cells are growing in the lab, and protected allows us to deplete those. And so altogether, you can make a pro-inflammatory sort of systemic and local tumor microenvironment that facilitates the T cells that we want to go into cancer. And so I’ll just give you one example. This is a patient we published in 2014. When we first started doing this, but this patient had a microsatellite stable Cholangiocarcinoma. You know, another gastrointestinal tumor. This is a liver metastasis, and not many mutations but we found one T cell clone in this patient. Here you can see this is showing in figure a this is a CD4 T cell and it’s in this V beta 22. This is sort of a family indicating the type of receptor that this particular T Cell has. Nothing special about V beta 22. It’s just what it had. And then on Panel B TNF is, is a cytokine that’s a pro-inflammatory cytokine that can sort of tell you if the T cells are trying to kill things. And here this is the protein that was mutated in the cancer and if you expose these T cells to the normal protein, which is present in the patient’s body, normally, the T cells of course, don’t react to it because your T cells don’t attack self right? They don’t attack your body for no reason unless you have an autoimmune disease. But in the presence of this mutated protein, they were highly active and this patient had a really an impressive response. And here you can see 10 years later this tumor still does not come back.

And then a final point I’ll make is that sometimes when we get TIL’s from an individual patient, we find T cells that recognize certain mutations that are shared between patients with colorectal cancer. So K RAs, and tp 53 are two of the most common mutated genes and colorectal cancer and they’re mutated more frequently in certain places. And so one patient has, let’s say, a K RAS G 12 D mutation, and their T cell recognizes that mutation, we can use that information to create a treatment for another patient who also has a K RAS G 12 D mutation if they have the same HLA type and so every time we treat a patient, every time we get TIL from a patient who has T cells that can recognize one of these we build a library and we can use those for treatment of future patients.

And so sort of just to summarize, big picture you know, the reasons why I think investigating TIL and TCR T therapy I realized I didn’t really talk much about TCR T therapy, but that wasn’t this was sort of the point of this was to give a general overview, but the reason why I think this is worth investigating is we do know the immune system is active, especially early on microsatellite, stable colon cancer. We know that most patients almost every patient, we can find T cells that recognize cancer-specific mutations. And the other thing about colorectal cancer is metastases are routinely resected for clinically indicated reasons right? So it’s an opportunity for TIL therapy if you’re taking a tumor out anyways. You know, it lends itself to this sort of thing because then you don’t have to have an extra surgery. Of course, as you all know, there’s this shift in colorectal cancer where increasingly younger patients now are getting diagnosed with the disease and we see a lot of them and, you know, when you’re thinking about immunotherapies, you know, we need patients obviously, in these trials who have a good immune system and are able to tolerate this. I mean, we’re always working to make our treatment more effective and we’re always figuring out how we can make it less toxic but right now it’s all investigational. And so it’s helpful if patients can can shrug off what we do. And then of course, as I mentioned, the shared hotspot mutations, K RAs and TP 53 are common in colorectal cancer and targetable with T cells, and most importantly, and we have anecdotal cases of till where we’ve seen very impressive responses and microsatellite, stable colon cancer, whether they be metastases in the lung or liver and so we know it can work and it’s just a matter of how do we make it work for most people. And I finally I had some frequently asked questions, but we I could go through these really quickly. And then we can address the rest of the questions in the chat.

So one question is: Can TILs be grown from primary colorectal cancer? And the answer to that is no. Because you know, the potential issue is culturing the primary tumors and media with the bacteria potentially causing contamination.

If you have a tumor harvest at the NIH, are you obligated to agree to go forward with cell therapy? If let’s say we grow your TILs, and the answer is no. Number one, it’s a separate consent process. So if patients are getting into harvest, then we have them sign a consent for that. And if patients are then going to get to therapy, the cell therapy, it’s an entirely separate consent, different discussion different you know, we’ll go through the risks and benefits and patients always have a choice. You can say, You know what I decided I want to do this and you can walk away and it’s absolutely your right to do that. Other patients choose to delay it, they say, Hey, I’m going to, you know, go on this trial, or I’m gonna get a different therapy instead and wait, and that is of course patients right as well and we can just keep the cells frozen. Now, the only thing to remember is if you do defer and delay the therapy too much, if something happens, the eligibility is compromised. And we cannot guarantee treatment, but certainly patients have the right to delay treatment. And we would go for it later if we could.

Can the two arms be done elsewhere? Not an option currently. For us because there are issues with sterility and the way we work with pathologists to confirm the diagnosis of cancer and our GMP rules. But in the future I mean that would be you know, if this you know with with melanoma the way this is working is it can be done anywhere, and it’s sent now to this central facility. Iovance will have it and so maybe someday, that will be what we do with colorectal cancer.

And then are there any financial considerations and the answer is no NIH work is purely investigational and voluntary, and patients are neither charged nor paid for participation in our trials. So I think that’s all I have some contact info as well.

Manju George 46:33
Okay. Thank you so much for that Dr. Klemen. So I just want to say that we will have Dr. Klemen come back and talk about specific trials. We are planning that. So this talk was generally like the idea was to provide a brief overview of everything that is happening, right. And then if you have specific questions about the trials, like that will be a different presentation. But we can take some of the questions and you can answer some of those right. So look at questions.

Dr. Nicholas Klemen 47:05
So we talked about international patients. Let’s see. So typically, how long does it take to go through the screening process? Yeah, so it’s it can be I guess, it depends on it little bit of a challenging question. I mean, if everything is completely smooth in the sense that the patient’s clinical status is good, and they’ve been off their prior therapy for like a month and I mean, we can we can go through pretty quickly. I mean, it certainly within a few weeks. That’s I mean, clearly the screening process can be done within a matter of weeks. Now, obviously getting to the end of the trial, I guess I’m not sure if that was exactly the question. If the question is how long does it take to actually get to treatment? That’s sort of a more loaded question. But purely to go through the screening process, it’s pretty quick. I mean, we can, you know, within a couple of weeks usually get an answer, at least for you know, as somebody that potentially would be eligible can come here for a visit. So I think if that’s the question, that’s the question then I think that would be the answer, but I can expand more, if you’d like to.

Manju George 48:22
Dr. Klemen, I have one question. Yes. Can people meet with you online? Do you do virtual visits at the NIH for the screening?

Dr. Nicholas Klemen 48:31
I chat with people on the phone I could do a virtual visit if patients had you know, you know, big picture questions about the protocol. You know, our research nurses are really good just because they can help. You know, we have a lot of every trial has a lot of eligibility rules, and there’s a lot of random things in there like like for example, steroid use chronic steroid use is a is a problem because we’re trying to increase your immune system and so if you’re on steroids chronically, like high levels of steroids, then that’s a problem. So the research nurses can pick up on those things. So the easiest thing is probably to do that but I’m always happy to just chat with somebody who, if they have questions, either on the phone or whatever. Okay.

Manju George 49:17
So there’s a question there is a lot of interest in the TIL trials. Can you explain how actually testing can be done for patients who are interested?

Dr. Nicholas Klemen 49:25
So for TIL HLA is not necessary because these are all your own lymphocytes. So they’re already HLA matched, so the HLA is baked in. The only time HLA matters is if you’re potentially using a receptor from somebody else. So if you have a KRAS G 12 D mutation, and you want to see if you’re a candidate for our TCR T trials, where we would use it a receptor that we’ve already isolated for somebody else, then the HLA matters and the advantage there is that you don’t need surgery. So we potentially can do things a lot more quickly. But that’s the only time in HLA matters if you’re doing TIL HLA doesn’t matter. Because they’re, they’re your own T cells.

Manju George 50:08
So basically, what he’s saying is that for off-the-shelf products, HLA Typing is important, but where you’re isolating cells from your own tumor, HLA typing, is not important.

Dr. Nicholas Klemen 50:19
Exactly. So there’s a lot of talk about car T and T and car T is sort of a thing that people know more about TCR T is basically the two ideas are you’re taking T cells and you’re giving them different targeting systems. And the only difference between car T is there’s only one thing in question which is does the surface of the tumor have the target? That’s yes or no. With TCRs? It’s does the tumor have the target? And is the HLA correct. So there’s two, there has to be two matches for TCR. There’s one match for CAR. And you might say, well, car sounds a lot easier when not just use that and that’s sort of a story for another day. But the long story short is you can’t target things like K RAS and TP 53 with a car. And there just aren’t as many targets for cars that are in solid tumors that you can go after without hurting normal tissues. So that’s the short version of that answer.

Manju George 51:12
So basically, you’re saying that for a cell surface receptor, CAR are maybe more useful like there are so I have to say this, we have the MSS clinical trials neighborhood where we discuss MSS trials for patients whose tumors are MSS. And we have an NIH lounge in colon town where we actually specifically talk about trials at the NIH and people have been interested in Car-T trials. So maybe for the next talk, we can cover the TILs and CAR-Ts. And maybe you know, because there are only a couple of CAR-Ts now but also the TCR Ts.

Dr. Nicholas Klemen 51:39
Yeah, that’d be good. Okay, of course. Yeah, I’d be happy to do that.

Manju George 51:49
Yeah. So the next question is, how does one know when to look for a clinical trial? My husband has stage four liver Mets and is having a good response to FOLFOXIRI Plus Avastin. Surgery on liver is scheduled for June 14, would a trial be something we should be considering for his primary tumor rectal at the anal average?

Dr. Nicholas Klemen 52:08
So yeah, I mean, there’s no more I don’t think there’s a right answer to this, but I would sort of say, you know, it seems like you know, the treatment plan is reasonable, but it’s never too early to start on, to start looking for trials. You know, a lot of folks may say, Well, you know, if the disease progresses, then come back, but you know, it’s certainly I mean, I guess what I would say is, I mean, anybody with stage four, colon cancer, or rectal cancer, there’s a there’s a higher I guess the the most important question to know is how high is the risk of reccurrence? And if the answer is pretty high, usually, it’s usually you know, 80% 70- 80%, sometimes less, but then, you know, eventually, you’ll probably need a trial and so I would start looking potentially earlier. Like I said, In the beginning, it doesn’t hurt to just meet with somebody and talk about things and they’ll say, hey, you know, maybe this isn’t the right trial for you, but we, you know, you should talk to so and so just to sort of get your ear to the ground and sort of know what’s out there.

Manju George 53:20
Okay, so I’m going to jump to another question about, again, the screening process. So the question is, can you go through the screening process while you’re currently stable for future potential to enter the trial?

Dr. Nicholas Klemen 53:33
Yeah. Yeah, no, I think that’s that’s potentially a good time to do it.

Manju George 53:39
Okay, so the next question in the comments says, I appreciated your comments on Twitter regarding liver mets sometimes responding to immunotherapy example in melanoma and for MSI-high CRC patients. Can you expand on this please?

Dr. Nicholas Klemen 53:54
Yeah, you know, this is one of these things. I mean, I don’t know. This is my opinion, but I don’t personally think the emphasis of liver mets is all that helpful. I mean, there’s a lot of clinical factors that can that are associated with how people do with a given treatment. And there’s been a little there’s been this data that showing it sort of started in melanoma showing the people who had liver Mets did worse than people who don’t but you know what, in melanoma, the way metastatic disease is categorized it’s there’s like M1A, right, which is a lymph nodes, like soft tissue metastases, and then there’s M1B which is lung metastases, and there’s M 1C which is visceral. And it is true that if you have M1 C, which would include liver, and M1 C is generally worse than lung which is worse than skin and lymphnode. But if you compare liver to other visceral, I don’t I don’t think there’s a difference. So even the initial thoughts in melanoma, this was true, I’m not convinced by now. And then if you look at colorectal cancer, I mean, if you look at sort of all comers in trials, you know, lung does a little bit better, you know, livers sort of in the middle, peritoneal is a little bit worse. But the other thing you got to remember about liver Mets is that the patients with the most indolent biology are being cured by surgeons, right I mean, if you present with a solitary liver met or you know a couple liver Mets and a surgeon cuts them out and it never comes back, then you’re never going to go to a clinical trial, right? And then you’re never going to see a medical oncologist. So the medical oncologist again, this is why everybody you know, we all have our own perspectives, right. And the problem with medical oncologist is they may be biased. They only see the people who progressed again but they don’t see all the people who are cured with surgery. And so if you count those people, then the liver might look a lot better. So we know in melanoma, and microsatellite instability, high colorectal cancer that the liver can respond beautifully. Is the response a little lower? Yeah, maybe but there are other factors that I think are more important. And ultimately, it’s just associations. But you know, at the end of the day, the liver thing, I just don’t think it’s very helpful because, you know, the bottom line is microsatellite, stable colorectal cancers. They don’t really respond to checkpoints, regardless of whether or not they’re liver Mets or not, at least, you know, to my knowledge, and with MSI colon cancer, you know, you’re certainly going to try checkpoints, whether or not you have liver Mets. I mean, you’re not going to, you know, throw that opportunity away. And so, I don’t think it’s, it’s something that people talk about, but I don’t think it’s that helpful.

Manju George 56:44
Okay, the next question is, is this something we should request at liver resection TIL therapy? So my guess is that based on what he said that’s not possible unless the liver resection is being done at the NIH, right?

Dr. Nicholas Klemen 56:58
Yes, yeah. You know, we have done that, where we can, you know, we can do it a clinically indicated liver resection and grow TIL from it if it’s done here. So that’s a potential option.

Manju George 57:14
Yeah. And then I do want to say that the person who got TIL therapy and you know, the long-term survivor, she’s actually in this call for CRC and she’s the admin for our group, the NIH lounge and she’s been exceptionally wonderful in sharing her experiences and we do have a couple of other people who have also tried TILs and you know, and it’s always good to hear their experiences too. So thanks Celine for being part of the call. Should I have a suspected CRC lung nodule harvested at the NIH rather than at the current at my current facility?

Dr. Nicholas Klemen 57:57
Yeah, so it depends on the size. But they could do and especially if it’s you know, biopsy-proven I don’t know if that’s totally necessary, but yeah, the answer is maybe right. That’s the thing with the NIH is, is there’s always right I have the asterisk for all of these potential scenarios. So the answer is maybe if it’s a very small, like half-centimeter lung nodule, it probably wouldn’t be sufficient to grow TIL and so if your doc just wants to know what it is and is planning to resect I think it’s reasonable, you know, they should just do what they want to do. But if it’s growing, and it’s, let’s say, a centimeter and a half, and that means it’s pretty suspicious that I would say, then, you know, we could do it here, potentially, if you know if the patient’s interested and eligible, but the answer is always sort of maybe so it’s, it’s, um, you know, definitely could reach out about that.

Manju George 58:53
Okay, so basically, what he’s saying is that, if the resection is just to confirm that its tumor and it’s really small, then the patient can have it at the local facility, but if it’s a large enough tumor, where you have the potential to harvest TILs, then that’s an option to consider the NIH. Yeah. Okay. And then is there data on the influence of the extent of liver disease on immunotherapy? Like to small mets versus 20 mets in addition to lymph nodes?

Dr. Nicholas Klemen 59:20
Yeah, I mean, so there is data on disease burden and this is sort of what I was alluding to. I mean, I think there’s there’s a ton of clinical factors that are important to sort of understand what is an individual patient’s biology look like? And you can look at you know, the number of tumors and size and overall bulk you know, I think that matter you know, I think there may be more of a relationship there. But we have seen people with really bulky large volume disease who have responses, but yeah, in general, again, the answer is, yes. Generally more disease is less responsive. But I would again, say in the case of colorectal cancer, you’ve either got microsatellite stable in which case really there’s no convincing data that checkpoints are effective or MSI high even if, if your tumors MSI high you’re going to want to try checkpoints, regardless of whether you have a large disease burden, but it is true, it is true that a burden is a negative prognostic marker.

Manju George 1:00:27
I think the next question about is about the Neo antigen cell therapy vaccine combination, the Gritstone trial that you and I collaborating. I was thinking that it’s past two o’clock so I was wondering whether you know, either we can include this in the next talk or if you want to say very shortly something then.

Dr. Nicholas Klemen 1:00:44
I’m happy to go over a little I mean, I guess you probably have to cut it off for the recording, but I will. Yeah, I would say that will be a combination. With our trials. It’s in process but I don’t know how much I’m allowed to say about this. But basically the idea is to make our some of our cells work better and in mice, basically, if you give cells do cell transfer and you vaccinate the mice, it works better than just doing the cells alone. So I know the recent Memorial Sloan Kettering paper in pancreas cancers, kindled a lot of interest in the vaccines and sort of there’s a long story there. But bottom line is it’s yeah, it’s to make our cell therapy work better. Okay, okay,

Manju George 1:01:27
I think that then maybe you have some idea of the kind of interest that people have that they like to hear about more, right, so that can help you with the next talk. So I want to thank all the participants and for all the questions and thank you Dr. Klemen. That was a very, very nice overview of everything and I especially like your introduction, I have to say.

Dr. Nicholas Klemen 1:01:47
Alright, it was a pleasure chatting with you, and thank you all for the opportunity. And like I said, feel free to reach out if you have any questions, happy to help out. Thank you very much. Yep. Okay. Bye bye. Bye.