Educated Patient Webinar: Deep Dive into TIL Cell Therapy for Those Living with Cancer


Ryan McDonald: Hello everyone, and welcome to today's live broadcast an Educated Patient Webinar: Deep Dive into TIL Cell Therapy for Those Living with Cancer. I'm Ryan McDonald, Associate Editorial Director for CURE. We are pleased to bring you this webcast presented by CURE and sponsored by Iovance. There are just a few important announcements before we begin. We encourage you to ask questions during the event, which you can submit by typing them in the Q&A box you see on your screen. You will be receiving a survey via email tomorrow, and as a thank you for watching the full webinar and completing the survey, you will be entered for a chance to win a Visa gift card. Now, let's welcome our panelists for today's webinar. First, I'd like to welcome Dr. Ben Creelan, a Medical Oncology Specialist and CLIP investigator at Moffitt Cancer Center, Dr. Yong Ki Hong, an Assistant Professor of Surgery and the Assistant Director of Surgical Research at MD Anderson Cancer Center at Cooper University Hospital, and Dr. Richard C. Wu, an Assistant Professor of Cutaneous Oncology at The Ohio State University Comprehensive Cancer Center, the James. And now, let's begin with our first topic of discussion, Deep Dive into TIL. I'd like to start with Dr. Wu, Dr. Wu, can you walk us through what is a TIL, and essentially what does it normally do in people?

Dr. Richard C. Wu: Yes. So melanoma turns out, it's one of those- it's one of the solid tumors that's very immunogenic. So, what I mean by that is, that it covers quite a bit of the mutations as a result of any chronic damage by the UV radiation from the sun, that's actually how melanoma develops in the first place. And, because it's all about how this mutation present in a tumor, and the tumor is constantly showing up these mutations to the immune system, that attracts attention of the immune system. And so, oftentimes, if you were to take a piece of a tumor on these patients, you can see that they're oftentimes infiltrated with a vigorous amount of immune cells and we call them a tumor infiltrating lymphocytes.

Ryan McDonald: Thank you. So Dr. Creelan, when you talk about a TIL, how does or how do cancer cells essentially overpower a TIL?

Dr. Ben Creelan: Well, that's the interesting thing, is that we know that most of the cancer cells that we create in our body, get eliminated, they get destroyed as soon as they're made, because our immune system recognizes them as foreign. So, if I tried to take Richard's cells and put them in my body, my immune system is getting rid of them immediately. Yet, somehow, these tumors [00:03:00] evolve to evade our immune system, and we know there are immune cells embedded in that tumor that recognized it as foreign, that we're supposed to get rid of it, that should have eliminated it just the same way as any other pathogen. So, how can we remove those cells from that environment, grow them to large numbers, and then give them back to the patient? That's really the fundamental concept here, is that you're taking a police or an army, a military, a part of your body that knows that this is a foreign invader, and you're just trying to retrain it, maybe make much larger numbers and give it back to the patient. But, those cells, those immune cells are our own, and they have the fundamental information they need to destroy the cancer, they just need some sort of activation step, they need some sort of a stimulation, and that's really where the money is here.

Ryan McDonald: Excuse me. So, Dr. Wu, how then, can investigational TIL cell therapies essentially prevent cancer cells from doing this?

Dr. Richard C. Wu: Actually, this was actually a topic of a laboratory research that I did when I was a graduate student at MD Anderson actually many years ago. And so, what happened is that once the TIL, the infiltrate- tumor infiltrating lymphocytes get into the micro-environment, inside the tumor itself, it has difficulty executing its task which is going up against the cells. Because, there's a- because the cancer cells express a molecule called PD-L1, and that molecule basically interacts with the PD-1 receptors on these T cells, which renders them ineffective, basically shuts them off. It's like putting on the- on a break on these immune cells so they can do their job. And also, my research for MD Anderson, which was published many years ago, also show that these T cells, when they get inside a tumor, for some reason, they're not able to fully differentiate into the potent killers that they're meant to be. So basically, there's a molecule that's produced by the inside of the tumor itself, that's inhibiting these cells from turning into the professional soldiers. I use that as an analogy that they can execute their tasks of killing the cancer [00:06:00] cells. So, the idea of a TIL therapy is that is to take these T cells out of this really suppressive tumor micro-environment, and take them away from these immunosuppressive signals, so that they can be extended to billions of cells. And then, and the ones- and since these cells they're grown outside of the tumors, and also they had- they also receive a very potent signal that would give in a laboratory to push them to differentiate to become really potent killers. And, I think that's really- that's why in some patients they appear to have benefited from the TIL therapy. And also, we have- and also there's a, there's also a very interesting ideas in other clinical trials, where they're trying to combine the immunotherapies, targeting the anti PD-1, PD-L1 signals, to make sure that when the TIL gets transferred back into patients, that they're not inhibited by these signals again.

Ryan McDonald: Thank you. And so, Dr. Hong, I'd like to kind of bring you into the fold as we're talking about TIL. And, there's probably a lot of patients out there, who, rightfully so may still be a little confused, or "Oh, my goodness, what is going on with all this the science"? So, in your expertise, and as you've worked on this with patients, how do you kind of explain to them, essentially, how these things are created?

Dr. Yong Ki Hong: Well, thankfully,I'm here with these two smart medical oncologists and surgeons that we think very simple- explained very simply. When I see a patient, for the first time, I just simply explain what TIL is, and it says it in the name, tumor infiltrating lymphocytes. So, you have billions of immune cells floating around, but why are the ones that are found inside the tumor special? And they're special because they have identified a target, we don't know what, but they have identified some target they have been attracted to and invaded, infiltrated the tumor trying to fight, but they can't fight it alone, it's like a battle. And they're suppressed by the tumor micro-environment, which tries to keep the tumor cells from being eaten alive by the immune system, so they shut it down. So, TIL therapy is simply excising a metastatic tumor, and slicing those tumors up and finding these special T cells, taking it to the hospital, or the lab, letting them recover and grown to billions of cells, and giving it back to the patient by preconditioning the body, to receive your tumor fighting cells without competing cytokines and regulatory cells. So, you get seven days of chemotherapy to really prepare your body to receive the cells back on day zero, [00:09:00] so that the only cells floating around in your bloodstream are cancer fighting cells, and they just rush through your body. And, to give it a little push, you give a little IL-2, to kind of really light the fire of the cells once they re-infused back into the body. And then, once the cells start to take off, that's all you need for the IL-2, and the TIL start going in- go to town and scavenging for tumor cells throughout the body. So, it's a beautiful technology and discovery by Steven Rosenberg, and all credit to him and we're all here because of him.

Ryan McDonald: So, kind of as we're talking about this section, essentially a deep dive into TIL, and I can open this up to everyone kind of here in the panel. But, as we're defining this, we're trying to talk about it and inform our patients, essentially educate them. For you three, kind of anyone, if you have an opinion, do you find it difficult sometimes with a topic like this where there's so much science in there, working with your patients and trying to ease any concerns they may have about, well, this is unique, this is novel, I've heard of chemotherapy, or I've heard of surgery, I've even heard of radiation, but this is just so new to me, how do you kind of ease those concerns?

Dr. Yong Ki Hong: So, I think at the end of the day, you got to explain to them what you're reinforcing back to your body. You're giving back your own cells, you're not giving- it's actually in my mind, safer than getting a blood transfusion. It's your own cells, and it's isolating cells that are important, that are cancer fighting, that are of your own, so you're not going to have any issues with it. And, the chemotherapy, we know that the purpose of it is just to pre-condition your body and not really to make you sick and toxic. It is just to bring down your competing regulatory cells, and adjust to really set the table for the cells that come back to your body. And then, the IL-2 purpose is just to kind of let it- like when you start a barbecue, you start a little match and then the fire takes off, sometimes the coal takes a little bit more fire, and then you give a little more fire and once the coal's lit, that's it. And, that's how I explain IL-2, you just need a little bit of a push to get the coal burning, and then once the coal burns, it goes.

Ryan McDonald: Dr. Creelan, do you have any insight on that as well, by any chance?

Dr. Ben Creelan: Well, it's a tough explanation sometimes, but again, like you said, the key thing is that you are getting your own cells back again. The infusion itself is definitely the simplest part of it, the pre-treatment chemotherapy, well, we just need to make space for the new T cells. If we just gave the cells by itself, our body would just say, "Well, I don't need these", so that's why we do need to give that [00:12:00] chemotherapy upfront. And, we also- just, again, we just need to promote those cells to persist and engraft, and that IL-2 is the same as stuff that the cells have been getting cultured in for the last several weeks. So, we just need to give you a couple of days of that, to help promote them persisting. Persistence is very important with the T cells, and that's just like persisting for everything is important.

Ryan McDonald: Thank you. Well, we've been talking ad nauseam about what is a TIL, what does it do, informing patients, educating patients. So, we're going to kind of shift gears a little bit, we'll start talking about treatment, per se. But, before we get into that, I just want to remind everyone who's attending and listening, don't forget, if you have any questions for our panelists, please be putting those in the Q & A box, we will be sure to get to as many as possible when we get to the Q & A section near the end of this webinar. Now, speaking of treatment, Dr. Creelan, who- which type of patients, or who are best suited to receive TIL therapies?

Dr. Ben Creelan: Well, the key thing is that we need a tumor to remove, and not all tumors are easy to remove safely. For example, you could have a very centrally located liver metastasis, which cannot be easily removed by surgery, but a lot of patients do have a tumor that's easy to remove, like a neck lymph node, or a very peripheral lung nodule. We know that those type of tumors make really good TIL, they grow well. And, the safety record is quite good for those types of procedures, so that's one of the biggest requirements. Maybe I'll pass it off to Dr. Wu, what other requirements do you think? When you're looking at a patient or talking to a patient, do you think about? Because, I can think about three more, but I don't want to- go.

Dr. Richard C. Wu: So, I kind of think of an entire TIL procedure, which we have a diagram up here, in which a lot of people actually like to see the picture. Because, I- they feel like they actually have all this procedure than words. So, I like to think of it as like a mini bone marrow transplant. So basically, the criteria that's used to kind of screen patients, to see if they're fit for transplant, is pretty much- very much applies to taking that same thing in TIL therapies. So, we want patients to have adequate physical shape, because especially [00:15:00] when the part where they're getting the chemotherapy, the seven days of chemo, and also the IL-2, those can induce significant physiologic changes, for working out. For example, the impact on the blood pressures and heart all these things, that if you're not in good shape, and this kind of therapies can potentially cause problems. And also, we don't want patients to have active infections, because with these, when they're getting a seven days of chemotherapy, by the end of the seven days, oftentimes, they're red blood- and they're infecting white- fighting white blood cells are very low. And, that puts them at a higher risk of infection, so they can now have pre-existing infections. And also, they should have adequate heart and lung function, and just because this- going through this procedure, there are some parts of it, that's tough on the body. So, I think, having those- having like an adequate baseline organ functions, it's important to reduce [CROSSTALK].

Dr. Ben Creelan: I think that's very important, I agree. Because, I work in lung cancer, so a lot of the time patients who are already on high doses of oxygen, they already have really bad COPD. It can be a challenge to get those patients through this kind of intensive therapy. And, I think what I kind of tell people is, it's kind of a high risk, high reward type of treatment, that you want to- you're aiming for the fences, if you're playing baseball. You're not going for a bunt here, you're not going for an infield single, you're trying to hit it out of the park with a durable remission. And, the batting averages are sometimes lower when you're going for that kind of a strategy. I don't know, what do you guys think about that?

Dr. Richard C. Wu: I once had a patient- so, once during my training at MD Anderson, so I remember that there was a patient that was a 17 year old, I think it was a high school student who had [INAUDIBLE] melanoma. And, at the time, this was a - the patient decided to participate in the clinical trials, and actually, we have some data to show that, that the younger you are, the more likely that you will have a lot of these TIL expended from tumors. So, that patient, when the treatment of this protocol and had a complete response, and then was able to finish college and actually got married and live a normal life. So, I think that's- I think it's important to kind of highlight that's the remarkable, or durable long term result response, everything with this longtime cellular therapy

Dr. Yong Ki Hong: So, I think [INAUDIBLE] was one component for this version, so we're trained to just, if we see bulky disease, it really just take out the whole thing, just give radical resection and give chemotherapy once they're recovered. So, I think it's a shift in mentality when you're a surgeon, you'd be going for a tumor harvest for TIL, the TIL is the treatment, [00:18:00] not the surgery. So, I've been asked by a lot of patients who have bulky axillary disease, take it all out, I'm like, "No, I'm actually going to take out one small nodule, that's all I need, and my job is to get you back on your feet with no infection, because I'm going to be giving you chemotherapy in a very quick turnaround, several weeks". So, I think that's a one difference, is that the surgery is just to go in with the least amount of insult to the body. So, just like Dr. Creelan said, for lung, lung surgery is very morbid, so is liver surgery, we do that all the time, but we want to go in with the least morbidity as well. We also have to factor in that, if you have a brain lesion, or a GI lesion, that the counts, your platelet counts will drop. So, there's a risk of you having some bleeding complications, so if you have a brain lesion, we would like to treat that ahead of time. So, if you have a GI, gastrointestinal lesion, we would like to re-sect that, because you have a high tendency of having a GI bleed or head bleed if those lesions were not pretreated before TIL. So, these are small considerations that I think we also factor in when we see patients.

Ryan McDonald: Now, interestingly enough too, I'm sure there's many people out there, perhaps who have heard about CAR T-cell therapies. So, Dr. Hong, Creelan, or Dr. Wu even, how does this treatment essentially differ from those established therapies, CAR T-cell therapies?

Dr. Yong Ki Hong: So, I think the main difference is that we'll talk about- so, we talked about TIL, so I guess the other option is to talk about CAR T. So, CAR T, the way they're formed is, you get a blood draw, and they do what's called leukapheresis, they check your blood and they filter out just the white T cells, and then they could be polyclonal, they're not responsive to tumor, but then they use a retroviral vector, meaning they put a virus into the T cell, and they inject a DNA sequence of the target that you want to target. So, the name of the game is what to target, so that becomes more important. So, it has been most successful in lymphoma and leukemia because of the CD19 CAR, it is homogeneous, it is universally expressed in all lymphoma leukemia, so it responds well. But, for TIL, there's less than 1% shared antigen between one patient to the next, so it's very heterogeneous. So, the name is what is the target of, let's say, a solid tumor that you're going to target? You have to have a homogeneous target that all patients can respond to. And secondly, you have to make sure that they don't have an off target toxicity. So, if some target on the body is expressed in [00:21:00] other parts of the body, you're going to have a lot of toxicity with it. The other big distinction is that the CAR T recognizes antigens on the cell's surface whereas the T-cells, by nature, respond to intracellular targets that has been presented through an MHC complex. The cell has to present to you the peptide sequence and the T-cell response, whereas a CAR T can respond to any surface. If it sees a surface lesion or antigen, they will attack it. So that's why it has been very beneficial for receiving 90-CAR because it is universally expressed with low toxicity, but that has been the holy grail for the CAR T research is what is the target that's going to be effective, universally applicable with low toxicity? And the offsite toxicity is right now the crutch that's really keeping CAR T from being really a resounding therapy for universal solid priority.

Ryan McDonald: Go ahead, Dr. Creelan.

Dr. Ben Creelan: Have a big track record in solid tumors yet that's trouble because, again, like Yong said, we need a target to go after for CAR T. The nice thing about TIL is your immune system has already decided what target is in your tumor. With CAR we have to decide on the target and so far there haven't been any massive successes in solid tumors. It's been a big challenge with CAR.

Ryan McDonald: Shifting gears slightly a little bit, we're talking about that patient journey, and I know we talked a little bit about what makes a patient eligible for this therapy so to speak in terms of like you said you have to have a solid tumor and it needs to be resectable in a sense but, Dr. Wu, if we're talking about patients and their interest in, say, enrolling into a clinical trial how do they kind of qualify to receive this therapy?

Dr. Richard C Wu: I look at solid tumor patients come into my clinic the same with everybody. I think we have to make sure that the patients have adequate physical safety. I think that's probably one of the most important criteria to be able to qualify for the therapy, and that they don't have any significant medical comorbidities that can increase the risks of complications on the therapy. So for example, any significant heart disease or lung disease or changing problems. Those are some of the issues that can potentially impact the eligibility for several patients, [00:24:00] and then the other big thing is make sure that's there's no current active infections because I think these therapies. There are some parts of therapy where a patient can be very vulnerable to infections.

Ryan McDonald: Now, obviously, before we get into the next question, just want to remind everybody again, question and answer. You can type in any questions you have for our panelists in the Q and A box that you see on your screen. Dr. Creelan, we've talked about infection. We've talked about the outside comorbidities, all types of side effects. Can you walk our audience through what are some of the more common and in fact rarer side effects that they may experience on something like a TIL therapy?

Dr. Ben Creelan: So the first thing that patients get is the side effects from the chemotherapy and that's going to be low blood counts, low hemoglobin, low white count, and that does make you at higher risk of getting an infection. In addition, you have the usual chemotherapy side effects: hair loss, fatigue, nausea, and that's usually manageable because the patients are coming every day. They're getting checked up on every day. So we don't want to let anything go untreated in that situation. The next side effects patients get are from the cell infusion itself. So you're getting these very hot to draw out cells that are about ready to attack a bunch of tumor, so they get a lot of fevers, chills, shakes, on the day of the infusion, and then the next kind of class of side effects that patients get that are pretty common is from the IL-2, interleukin-2 and that's very much like a flu-like syndrome for the couple of days that they're on the IL-2. You have the same thing. Fever, chills, and you also get something called capillary leak syndrome where your blood vessels are leakier than normal when you're on that medication. So you get puffy. You can actually have water build up in your lungs and so we often need to treat patients with diuretics, water pills, when they're on this, and they're being monitored in the hospital at most centers after they get their cells. Those are the most common things.

Ryan McDonald: So actually kind of as we're talking about side effects, one question came in from the audience and I think is good to kind of bring up now and not wait, but someone wants to know could this treatment perhaps result in an autoimmune type of response that cannot be treated [00:27:00] or stopped?

Dr. Ben Creelan: I think, theoretically, that is less than one percent. You can get hypophysitis, your pituitary gland being autoimmune, and requires a lifelong hormone replacement but that's less than one percent. That is quite the theoretical risk, and a lot of times you get this lifelong vitiligo which I think, historically, is thought to be a good thing. When you think of side effects everything kind of seems a little bit scary, I get that, but I think one thing to keep in mind is that if you graph out the timing of the side effects, they are all within the hospitalization which is about two weeks from start to finish and so by the time you leave your side effect profile is pretty much gone. Whereas if you do the current checkpoint of the monoclonal antibody PD-1 inhibitors, you can get side effects down the road. You don't know when or if you're going to get it but with TIL it's fairly predictable, with the IL-2 toxicity, fairly predictable. Your blood pressure drops, we support with fluids, your oxygen main goes up, we give you oxygen, but then when you're done with the treatment we pull all that fluid off of you so it's all transient, and so I think that's one thing to reassure the audience is that it is an expected side effect profile that is reversible.

Dr. Richard C Wu: But just to add to that, so I think if you were to compare the autoimmune side effects of the current immune checkpoint therapies that we're using things like that KEYTRUDA or OPDIVO, those therapies work by essentially taking the brake off your entire T-cells in your body whether or not they are reacting to tumors or not and some of them could be reacting to your own organs so that's why we see at least 20% of patients having autoimmune side effects. Whereas with the TIL therapies, you're only activating the cells that the immune cells are specifically reacting to the tumor. I think the instance of autoimmune side effects is much less I think with the TIL therapy. Although there is always a risk in terms of rare side effects. There was this one side effect that was probably four months recently that involved inflammation in the eye. That can happen but the frequency of that is one percent or less.

Ryan McDonald: Dr. Creelan, you had something?

Dr. Ben Creelan: Well, I was just going to say that's kind of what drew me to this field is this idea that it's a one-time treatment and in fact, it reminds me of this motto for a weight loss clinic I saw. We want to see less of you, and the same thing's true in our field too. Honestly, as medical oncologists Dr. Wu and I, we want you to be doing well. We don't want you to be hooked up to an infusion every three weeks or every six weeks which is the way modern medical oncology works. [00:30:00] You're going to have point of service visits and you have patients coming back every three weeks, every month to get their mandatory infusion. No. As medical oncologists we want patients to do better and we want to see less of you actually. We want to know that you're doing well and that you're not kind of signing up for the next year to these frequent infusions. This is a one-time treatment. If it works it works.

Ryan McDonald: Expand on that a little bit, Dr. Hong, if you don't mind. Dr. Creelan talks about this one-time treatment. For a patient out there, Dr. Creelan just said one-time treatment. What does that mean? Can you expand on that a little bit?

Dr. Yong Ki Hong: I like to echo Dr. Rosenberg's words that this is living and breathing treatment. So the moment that the cells left the body at that time of surgery it has continued to grow, live, expand, and it's given back to you still living. So the cells are your own cells and the cells divide and the cells surveillance your body. They become memory cells and they continue to surveillance. They divide if they see a tumor and if it finds a response it will regenerate, it will draw other chemokines to attract other T-cells. So once that's killed it off it continues to become memory cells. I know everyone has seen the movie Matrix so I kind of use that analogy of the sentinels. So they kind of roam around quietly and then they just kind of all of a sudden, you see a tumor and they get active and they swarm the tumor. That is the perfect imagery of TIL because they are living, breathing, and they're constantly surveilling the body and the moment that it sees something it attacks. I think that's the best way to describe it. I'm sorry for the Matrix analogy but that's the best way to say it.

Ryan McDonald: Go ahead, Dr. Wu.

Dr. Richard C Wu: Just to add to that. The TIL therapy, I like to think of it is that you're recruiting immune cells or, aka, professional soldiers that know what they're doing. Once you infuse them into the patient's body then these soldiers they know where the enemy is exactly. Whereas if it's other kinds of therapies, essentially you're recruiting not only the professional soldiers but also the nonprofessional ones that may be the reserves, and some of them they get shipped into the battlefield and they don't know what they're doing. So with the TIL therapy at least it's once you get these cells into your body then these cells they know exactly where to go.

Ryan McDonald: We've been talking [00:33:00] about TIL and we've been saying who qualifies, clinical trials, best options. I want to talk about kind of the data that's available and what is out there and what it's shown. Dr. Wu can you kind of talk about what the current data has shown in terms of TIL therapies and their effectiveness?

Dr. Richard C Wu: Yes. So we're going to look at which disease setting that we're seeing the efficacy of the TIL therapy. The TIL therapy had been tested in mainly for melanoma but also other types of solid tumors such as cervical cancer, lung cancer. I know that there's ongoing clinical trials in those areas as well. So my specialty is melanoma so I can speak to my field. So I know that when it's given to patients that's for the very first time in tumor naive settings, I think we response rate, it's between 40 to 50 percent so almost close to half the patients have benefitted from these therapies, and some of the responses that we see can last years, and there's some patients that never have experienced relapse from the cancer, or melanoma after they got this treatment. In the patients that have failed the immune checkpoint therapies, right now we don't have good options for those patients especially if they don't have a mutation copying that in their tumors. Right now, outside of a TIL, the other therapies that we have doesn't really improve patients' prognosis. So when TIL therapy is tested for the melanoma patients that have failed the standard immune checkpoint therapy such as OPDIVO, KEYTRUDA or YERVOY, we see response rate close to around 32% in those patient populations so about a third of patients benefitted from the TIL therapies who have failed the previous immune checkpoint therapies.

Ryan McDonald: Dr. Creelan, Dr. Wu was talking about the melanoma data and I know you specialize in lung cancer so do you mind kind of breaking down kind of what's currently available or at least has been shown in terms of effectiveness in the lung cancer population?

Dr. Ben Creelan: So we're seeing similar facts that a proportion of patients, a chunk of patients. Maybe 25% of patients can get these meaningful responses, durable responses with TIL treatment after progression on previous chemotherapy, previous OPDIVO, KEYTRUDA, other types of drugs. So I think that's really exciting for our field because what our gold [00:36:00] standard is for the relapse refractory lung cancer, lung cancer that's kind of been through all the other treatments, we're looking at response rates at ten percent. We're always talking about months with those patients and not years. It's nice to actually be talking about the potential for years rather than just months, and along the same lines, it's kind of shown up across these cancers. We see data in cervical cancer. We see data to answer some questions in breast cancer. There was a really exciting case presented by the national cancer institute a couple of years showing a durable response with TIL in breast cancer.

Ryan McDonald: Well, we're getting a little more than halfway through so just a reminder to the audience, if you haven't submitted a question yet and you've got plenty to think of, shoot them in the Q and A box. We'll do our best to get to all of them.

Dr. Ben Creelan: Very excited to answer that.

Ryan McDonald: What's that Dr. Creelan?

Dr. Ben Creelan: I see some great questions here. Very excited to answer them, some of them. Some of them are very good. I don't know if I'll be able to answer them personally.

Ryan McDonald: Dr. Hong, I kind of want to talk about ongoing clinical trials and what's kind of out there so to speak. So can you kind of talk about what's available to patients, trials that are actively recruiting patients, and if I'm kind of curious how to join can you walk me through how I should go about doing so?

Dr. Yong Ki Hong: So I think the good news is that the TIL technology has been available for now over 20 years and I think it's just about to go to the FDA so I think the good news is that the TIL therapy should be FDA approved for melanoma, hopefully, this year but there's still ongoing clinical trial. First looking at TIL as a first-line treatment meaning that everyone likes to give the checkpoints upfront and if you fail then you think of TIL. If you think of TIL as a first-line therapy and give pembro or OPDIVO with it that allows you to take the monoclonal antibodies to take the brakes off and allow the army of T-cells to be in your body and so then consideration being upfront with pembro and then there's other newer trials looking at genetically modifying so there's no PD-1 expression so you don't need the pembro. So these are new genetically modified TILs that doesn't require these extra treatment infusions that may simplify things. I think these are all on the so if you're a patient, and I see a lot of very thoughtful patients asking [00:39:00] about different cancers, the best way to do if you're looking for a trial go to and type in your cancer and type in TIL therapy and you should get a list of national sites that available clinical trials but right now the most promising treatments are in areas of melanoma, head and neck, and lung cancer, and if you think about it all sort of originates from sort of an insult that for melanoma so thought to be EV related for cigarette smoking, for lung cancer, and head and neck. So I think there's a lot of physiologic and epigenetic insults that your body takes from these injuries so they have a lot of mutations. So the more mutations you have, you have a higher chance that you're going to express a protein that is not yourself and better chance for your immune cells to recognize it. So I think that really the problem trying to make all cancers be immunogenic. Some are considered cold tumors. So pancreatic cancer, liver cancer, stomach cancers, they don't really express any targets that the immune cells react to and they don't have a lot of mutations so a lot of the mutation rates are the highest in melanoma, and lung cancer, and head and neck so that's why it's the leading candidates for it. I'm sure Dr. Creelan can expand on this but the breast cancer and triple negatives have the most amount of immune response of the different types of breast cancers so those are the thoughtful cohorts that may be the future but it really has to stem from, does the tumor create enough peptides or antigens that may make it recognize from your body?

Ryan McDonald: Go ahead, Dr. Creelan.

Dr. Ben Creelan: Well, I think the key idea although is that, at least in the trials we did, we see patients who aren't supposed to respond to immune checkpoint inhibitors, patients with low mutation burden, low tumor mutation burden. They can still respond to this treatment. I think most people's tumors do make some T-cells that recognize those cell tumors and the key is to get enough material, grow it to enough cells, and then hope that a lot of those cells actually do target the tumor cells. One of the truths of this is that when we grow the immune cells we don't know for sure if those are the tumor-specific immune cells that we're growing. It's kind of a competition to see which cells will grow fastest, and we could always risk growing bystander cells that aren't actually targeting tumor. [00:42:00]. I think for the patients that tend to respond, those are the ones that we did get lucky, and we were able to grow those tumor specific cells. And really, in theory, any cancer, this could potentially work for. But again, you want to play the numbers game, and the ones that have the highest numbers of tumor specific T cells are probably the ones that are going to respond the highest.

Ryan McDonald: Well, I think we're going to start opening up the audience Q&A. I know, obviously, people have been submitting various questions, and we've been filtering through them and continue to do so. We still have about 15 minutes left. And I appreciate everyone staying on with us this evening. So, keep those questions coming in. I'm going to start with Dr. Wu. We've been talking about TIL, obviously, and different solid tumors that TIL works in best in clinical trials and everything. But there was a question that came in here that I think some people might be also thinking too. Is there a possibility that tumors don't have TIL is present in them? And if so, which ones are less likely to not have TILs?

Dr. Richard C Wu: I think my other colleagues who may have already answered part of that question. I think one of the requirements for sufficient TIL present inside of a tumor is that the tumor has to be immunogenic. And meaning that it presents themselves with the markers they're very different from the normal cells, such that it catches the attention of immune system. And, of course, this phenomenon could potentially vary from patient to patient. So that's why TILs is very much a personalized therapy, and particularly for the more immunogenic cancer types, such as melanoma and lung cancer, where these cells have lots of mutations, and they attract the attention of the immune system greatly. That's where we see a lot of promise of TIL therapy for those cancer types. I know that there were some audience members that have asked about prostate cancer, I think unfortunately, prostate cancer is not the more immunogenic cancer type, actually, if you were to take a biopsy of a prostate, and look for immune cells, actually, you can barely see anything. And I think part of it is that the mutation burden in this prostate cancer cell is not as much as other solid tumor types.

Ryan McDonald: So Dr. Hong, [00:45:00] I had a question come in. We talked about clinical trials, and getting access to them and all, but say, if I'm going to a certain cancer center that doesn't have an active TIL study, how do I find where the closest one is, and whether or not I'm going to have to really travel far to access one?

Dr. Yong Ki Hong: Throughout the pandemic, we've actually treated patients several states away. And that's the beauty about this Till therapy is, even if it's a travel, you really need to make two travels. One is for the surgery, and one is for the treatment. And after that it's a one time treatment. So it's worth the trip. And it's easy to find where your nearest treatment center is. With now telemedicine, you can initial consultation, that's what I do, I do initial consultation. So really get the information, save them a trip, once they're ready, and they understand we bring them in for surgery, we send them back home or even stay in a hotel or with family nearby, and they come back for the treatment they go back for good. I think that's the one benefit of the TIL therapies. Even though it's a little far away. It's not like you had to keep coming back like radiation treatments or chemotherapy treatments, you have to keep coming back, it's not that. And really to answer a lot of the questions for the other patients, if you can imagine the people that fish, if you throw a big net, and then you gather that net, and there's not much fish in there, you're not going to get a lot of different fish to expand. There's only one type of fish or two type of fish and that's it. If you can stimulate the water and chum the water then all the fish comes in and then you now scoop them out of the water, then that net has not become a big diverse polyclonal population that you now expand. That's how you think about what good cancers to offer TIL. The ones that have no fish in it, if he harvests a tumor, there's not going to be much immune cells to really expand on, and reactive ones. But if you stimulate the water and then you capture that, then that's going to be the more robust treatment. I apologize if that's too simplistic way of thinking about it. But that's really meaningful of why we don't offer it, it's not that we don't want to offer it's that it's not going to be as helpful.

Ryan McDonald: Questions coming in. One question, Dr. Creelan, I want to throw your way. Can you shed any light on the costs for a patient going through this therapy? And what potential options are out there to help with anything in that arena?

Dr. Ben Creelan: Yes, the trials will pay for the expenses that [00:48:00] insurance companies will not cover, which is most of it. So the sponsors of the trial are obligated to obviously pay for the TIL, the research related expenses. But the big expenses, I find, are exactly what Dr. Hong just mentioned, it's a travel, the staying locally, staying within 30 minutes of the cancer center for the next several weeks, while you're getting monitored. That can run around $4,000. We always tried to make the sponsors of the studies include the potential to get those invoiced. But not all trials can afford that. And there's also caregiver expense too, because we know this takes a village to get a patient through a big cancer treatment, it's just like a surgery. Having a caregiver taking time out of their general schedule, taking FMLA filling medical leave, sometimes. Those are a lot of the expenses that accrue.

Ryan McDonald: Dr. Wu, a question coming in. And you Dr. Creelan, and Dr. Hong have been answering this almost throughout the webinar, but looking ahead, looking forward, what are some of the potential future, on the horizon of TIL therapies? What's next for patients out there who might not be qualifying now, but they want to know, can I qualify in the future? What's next for them?

Dr. Richard C Wu: I think of TIL as a platform technology. Right now, we're still at pretty much the tip of the iceberg for this technology, and there's still so much that we can do to improve it. Right now, we're just giving patients pretty much a mixture of cells that, with the hope that someone will be reacting and will be specifically attacking the cancer itself. But some patient may not be as lucky. I think there's an ongoing effort to try to find new ways to grow these T cells in order to improve the process, such that the cells that's grown out from the patient's tumors are more specific to fight the cancer specifically, and also recognize it specifically. And I think there's some emerging technologies that had some promise that could potentially significantly improve this technology in [00:51:00] the near future. And also, because we isolate the cells on the patients, I think this opens up a tremendous opportunity for us to look into ways to modify these T cells. Just the same way that we're making the car T cells, we're taking the patient's immune cells out of their body and then genetically modifying them. And right now, there's an effort to see if we can remove that PD one receptor and from the TIL, so that when these cells are infused in the patients, the new cells no longer get the negative signal from the tumor. I think, right now, we're just at the very tip of iceberg. There's just so much potential for the technology to be further improved in the near future. And my hope is that as the technology matures, even more then we can get through more and more patients into the study. And I think while my hope is that we can somehow make this treatment, it can be given on an outpatient basis as opposed to inpatient. But right now, because of a need for IO2, it's not really feasible, but I'm hoping that in the future maybe someone will develop a less toxic version of IO2, and in that case, that can make the TIL therapy able to be given on an outpatient basis.

Ryan McDonald: Now, we're getting close to the end. I want to get this question in there real quick, though, and then we'll get everyone's parting thoughts and last thoughts. But Dr. Hong, I want to give our audience some options. What are some organizations or advocacy groups out there that can help people if they're looking for more information on TIL therapies or what to expect? Do you have any that you can share and provide with our audience?

Dr. Yong Ki Hong: I think the NCI is a good site for all the new trials for trial information. I think if you have more informations on TIL I think IO Vance is a good site that has good information on what TIL is, what the nearest sites are, there's also the Melanoma Foundation. I think there's a lot of support groups for melanoma and lung cancer head and neck and different cancers have a foundation. And I think they're developed by a bunch of really caring individuals, that really want to help other peoples with similar cancer. So I think these foundations of your respective cancer are the best source, I think, of all the newest information. And also to think outside the box, I know Dr. Creelan said, travel is important cost, and I know, one of our patients had free travel by volunteers who are former pilots that would fly patients to get treatment. [00:54:00] He got flown from Virginia to New Jersey free what this chariots for hire company. These are lots of people out there that really want to help others. And I think if you look out for them, I think there'll be a lot of resource.

Ryan McDonald: I'll go around the horn, so to speak, Dr. Creelan, if you don't mind sharing some closing thoughts before we end here.

Dr. Ben Creelan: Well, again, I think it's a promising new pillar. It's a fifth pillar of our cancer treatment, you've got chemotherapy, you've got radiation, immune therapy with new checkpoints, and you've got surgery, then there's that fifth pillar, which is really cell therapy. That's, I think, the next wave to hit what we're doing.

Ryan McDonald: Dr. Wu, any last closing thoughts you would like to share?

Dr. Richard C Wu: Yes, I think there's a very exciting trial, which I'm having at Ohio State, which is looking at the use of TIL as an earlier stage disease for melanoma, for stage three patients. And we're also looking to isolate TIL, not from the tumor itself, but also from the lymph nodes involved by the tumor. That was actually based on a recent study, which they showed that the majority of T cells recognizing the tumor is actually in lymph node, and not so much in the primary tumor that was based on a study. I'm actually pretty excited about this trial, because, it this worked out, that means that patients probably don't have to go through a very big surgery to remove the primary tumor, all they need to do is just have a lymph node taken out and fulfill extension. And this study is recruiting patients, so if you have any interest, if you have a stage three disease melanoma, particularly, I'm very interested to see if you qualify for this trial.

Ryan McDonald: Thank you. And Dr. Hong, any closing thoughts before we end?

Dr. Yong Ki Hong: Yes, so I would say that this is an exciting time, I think the future is very bright. As a surgeon, and as chemotherapy docs and radiation docs, our job, I think, is to control the disease. But until now, immunotherapy, we're talking about cures. And I think that's an amazing concept of stage four disease and cure, those two have not been spoken together for a long time. And I think that is a real possibility with cell therapy. And I think the future will only get brighter as smart people on this webinar will continue to help lead the way. And I think there's only more things that's going to be available for patients, and I know a lot of the patients [00:57:00] I've seen in the chat room, I feel for them and then I think the cell therapy will be coming for their cancer as the technology and the science evolves, but I think the future is brighter than it's ever been.

Ryan McDonald: Well, unfortunately, we are out of time. If you'd like to watch this webinar again, it will be available on the Webinars On Demand page on within the coming days. I do want to thank our panelists, Dr. Wu, Dr. Hong and Dr. Creelan as well as the audience for attending and participating in today's event. I would also like to thank Cure and our sponsor IO Vance, for making today's educational webcast possible. Now, don't forget to check your email tomorrow for the survey, to be entered for a chance to win a gift card. Thank you all for joining and we'll see you next time.

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