CAR T-Cell Therapy and the Future of Cancer Treatment


Hi Welcome back to the healthcare triage. podcast this episode of the healthcare cheers. PODCASTS is sponsored by Indiana University School of Medicine whose mission is to advance health the state of Indiana and beyond by promoting innovation and excellence in education research and patient. Care School of Medicine Leading Indiana University's first grand challenge the precision health initiative with bold goals to cure multiple myeloma triple negative breast cancer and Childhood Sarcoma and prevent type two diabetes and Alzheimer's disease. Today we're GONNA be talking to Cherie Virago professor of medicine and medical molecular genetics and also director of the stem cell program. I use school of Medicine. He Generals General's GonNa talk to us today about stem cell. Therapy and car T.. Therapy in particular which you may have heard in the news but before we get to that. Let's start with some basics first of all. Welcome to the program program thank you. Can you tell us in general what it means to be not only a professor of medicine but a professor of medical and molecular genetics so medical Michael Molecular Genetics. It's a very broad term It's it's really looking at the molecular basis of disease Not just inherited a disease but Many of the diseases have a molecular basis. Even if they're not directly inherited had he actually look get to the molecular basis. What kind of research technologies are you using? The biggest technology at the moment is Sequencing genes particularly in in terms of Chewers in my area sequencing can cell's genome to identify particular mutations. That could be targetable identifying mutations Sion's that in future could be Way We could design drugs perhaps decided Also there are ways of personalizing Medicine in a way Way We can identify Because not all cancer even the same kind of cancer is not all Homogeneous there's a lot of heterogeneity so if you can identify certain mutations in a person's at cancer cell you may be able to target that specifically perfect for that person's cancer as opposed to all the people with that kind of cancer. So how do you train to do this kind of work so in your career career how what did you do to get to this point. Well I guess there are various ways of getting there the way I got there. I trained actually in Australia Did all my hematology. Aw called you training in Australia. And then I did a PhD. That was more related to stem cell transplantation rather than molecular medicine at the time and then I moved to Ohio state where I stayed there for about six years on faculty and then the opportunity came to lead the transplant program. Ram At Indiana University. So I moved there in two thousand six. So we're talking about treating cancer. Is it all kinds of cancer or specific kinds of cancer. Turner accident well as a stem cell transplant. we're really focusing on hematological. Kansas blood cancers So leukemia multiple myeloma lymphoma. These are the ones that are amenable really to stem cell transplantation. You talk about what the differences are between those three short so It's really the cell of origin or the origin of the cancer so leukemia we're really talking about Cancers of blood stem cells the bone marrow in multiple myeloma. We're really talking about Cancer cells plasma cells which really part of the immune system in lymph falmouth with talking about cancer cells that are also part of the immune system that the less differentiated cells than the Coloma. So what what causes these. What makes someone developed one of those types of cancer? Well that's a really good question and we don't know all the the answers to that but It the it's silly as with other Kansas to I'll just blood cancers there are Hits in the genome of the the cans of the cells that turns them on to become cancerous essentially and so once they become cancerous. They just start growing multiplying without controls trolls. That the gist of it. Or Yeah. That's basically it they. They're able to multiply without control but they're also able to survive better They have a survival advantage compared to their normal counterparts talking about the history of treatment of those types of cancer. Like what do we do. And what are we. What are we got into now? And specifically of course what is stem cell therapy. Happy at the end. Yes so you know historically the we have been treating and we still the do treat These cancers with conventional cytotoxic agents these agents are essentially cellular toxins that cause DNA damage to the cells and as a result they The cells sells died and they because cancer cells tend to divide more frequently or more rapidly than normal cells and these conventional channel cytotoxic target the proliferating cells more than the Doman cells. So we're able to Mo- selectively kill cancer cells. But they are. They also affect normal cells as well as things have evolved We are now able to. We learn more about the genetics of the Kansas. His when now able to design drugs that particularly targets in pathways molecular pathways. That these cancer cells depend on so Treatment has become Less toxic to the to the patient in general so we're trying to target specifically just killing the cancer while not killing other other rapidly or any other kinda cells in the body. So what is then stem cell. Therapy like what. What's the difference between what skyping there and then going all the way to say? We're GONNA do a stem cell. Trance have so in some cases not all Kansas but some Kansas are also amenable to stem cell transplant therapy. And they're really too broadly. Speaking to approach is one where we use. The patient's own stem cells called tolerance stem cell transplantation. And where we use dona cells or allogeneic stem cell transplantation so with autologous transplantation plantation would really reverting back to the classic cytotoxic approach way we give very high doses of chemotherapy to Kill Oh as many cancer cells as possible. One of the side effects of this is that it will also cools a permanent damage to the bone marrow of people without stem cell support report. They would Essentially die of marrow failure so to collect stem cells. I there on stem cells assuming their stem cells not diseased. Then when you can give high dose. Chemotherapy give back stem cells and allow the marrow to recover so I have a couple questions there first of all. How do you get the stem cells? Out So stem cells live predominantly in the bone marrow But they do circulate the blood so you can either collect directly from the bone marrow but more commonly family today in the autologous approach we give growth factors which can move stem cells to circulate more in the blood and then we collect them. I'm by a process called a ferocious. Where basically they are collected a blood donor machine essentially that will collect them from the blood? How do you how do you how are you sure? You're not collecting cancer cells at the same time you do Some of these stem cell products will be contaminated but to some extent by cancer sells but it seems that most relapses after autologous transplantation occur not because of contamination. But because you really the the chemo a high dose chemotherapy that you've given has not killed the last cancer cell in the body. So how are you also assured that the stem cells are not. Can't where's the cancer come from. If it's not coming mm from stem cells as the simpsons or what about the sort of the the. He met a poetic stem cells. That give rise to the sherm tie. He met a point system. MM-HMM SO For example in multiple myeloma these inadequate ext themselves are not cancerous. Okay and in lymphomas Somali. They are not not cancerous. Can you just give us just a brief description of what the poetic system is so the Humana poetic system is essentially all blood forming cells and immune cells so the very primitive stem cells that give give rise to the humanitarian existent. They give rise to white cells red cells platelets as well as the components of the immune in systems such as B. Cells. T. Cells natural killer cells. We're just trying to figure out in my head and where it comes from. Because if if the are the white blood cells coming from the bone marrow in the stem cells though in development I it depends on the Canada Essentially for example if we take multiple well my Lama so the Within the immune system one cancer cell becomes Transform to become malignant and phones a clone in that clone of actually expands and has sub clones of its own and that's really the cancer but that's not arising from a in the actual stem cell of the very primitive stem cell that gives rise to all the blood forming cells in the Merrill. So then the say let's take lymphoma for instance or your leukemia dumb bass boats. It doesn't matter my head D- it's not that they're coming out of the bone marrow or or out of the stem cells cancerous cancerous. It's that you already have lymphocytes which then becoming cancerous yes basically and then they. Just keep dividing and reproducing amongst themselves exactly. Now that's different to a myeloid leukemia for example with the cancer is really in the stem cell. In the Humana poetic stem cell itself so allergies eligible so Atallah. Transplantation is really not Appropriate full most of these patients. And that's the way you really need to use a different approach. which is the allogeneic stem cell transplant? I alluded to before okay. So that would be like we again. You try to wipe out everything. But you're bringing because the stem cells themselves are somewhat cancers. You'd have to go to somebody else to get. In addition the allogeneic transplantation is also a form of immune therapy because Within the stem cell product. That you collect from Dona. There are immune cells and these immune cells will see the recipients tissues and actually cancer as foreign foreign and mountain immunological attack. Why want to come back to that okay but I have a question before? How do you actually put the stems back in? I mean you can't inject them back into the bone marrow do you you know we inject them actually into the blood. So it's like a blood transfusion germ and they have receptors Where they can locate essentially the bone marrow niche and Go there and proliferate do they go back to sort of all bone marrow or do they preferentially had two different bones. Well I think the in the bone marrow Not old bones are parts of the bones Marrow producing so they will go to the mirror. Producing which which phones are producing primarily primarily the spine the pelvis ribs the proximal pots of the long bones. That's interesting all the medical school and I didn't know that okay so Okay but you mentioned. Before that allogeneic stem cell transplant can be immune therapy because those blood cells will go into tech. Why don't we do that more often than empirically when you look at what? We've tested. Compare tolerance and allogeneic not all cancers Necessarily amenable to allogeneic will respond to the immune therapy associated with eligible transplant as well. What are some of the risks? Probably the main risk is graft versus host disease graft versus host disease is really way the immune cells of the attack the normal body tissues of the recipient so that effect is really a double edged sword so we wanted took effect. They'll kill the cancer but we don't want it to attack the normal body tissues. And how does that manifest acute graft versus host disease occurs surly on in the first Maybe two three months after transplant and That manifests The target organs are basically skin got got and live up. So patients may manifest as a skin rash But probably the most serious manifestations would be guests during testing Estelle with the diarrhea vomiting. And how do you treat that. Or how do you prevent it so treatment at the moment. is is Is really just targeting the immune in system in general trying to damp down that immune response so we use immunosuppressive drugs Well we using suppressive rugs to try and prevent it but then we add more immunosuppressive drugs to try and dampen down that response When it occurs so if you get an allogeneic stem cell transplant? Is it that you need to treat the immune system or suppressive for a period of time while takes root or do you have to wind up being UNAMUNO suppression for life generally we use Immune suppression drugs for about the first one hundred days and typically we would start tapering the immunosuppressive drugs of the next three months of by about one hundred and eighty days is You know people should be coming off that now. If they develop graft versus host disease during that time they will require to remain immune suppression for longer and That can vary because there's also another form called chronic graft versus host disease which can also occur and Again depending on the severity some people can remain on immune suppression for many years and potentially life so how well does stem cell therapy work depends on the cancer for example if Lymphoma is sensitive to conventional chemotherapy dosing In the relapse setting then we can probably cure about fifty percent of patients with autologous stem cell transplantation. In leukemia we probably curing during about maybe fifty percent of patients with allogeneic stem cell transplantation. But that depends a little bit on the Risk factor of the leukemia itself. Because again it's not a it's not a homogeneous Disease so we mentioned immunotherapy before. But certainly that's something we're hearing being more and more about the new so what what technically is immunotherapy and how does it differ from say chemotherapy. Well chemotherapy is essentially use of a drug of some sort Now Immune therapy is trying to use the patients. All the donor's immune cells to attack and kill cancer cells so we mentioned how donors cells could be used. But how can you use a patient's own cells to attack cancer. Early studies really looked that Giving cited kinds which has just really proteins That Stimulate the immune system at trying to broadly and crudely stimulate the patient's own immune system in the hope that in some way we can will the patient's immune system can kill cancer Hansa however Over the years we've learned that Cancer cells can actually mosque themselves and dampen down any immune attack back by the patients on immune system so there are now what are called checkpoint. Inhibitors which have been approved in a number of different doc. Kansas way we can block that Moscow effect so that the patient's own immune cells can attack the cancer. Can I get you to talk a little bit more about. What do you mean by masking asking affect? What are the cancer cells do so they can They do it in a variety of different ways that we know of They can express A molecule on their surface surface that actually inhibits the immune cell so the cellcom attack. They just naturally early figure this out and that just that just evolution or wh- what. Why would that happen well? That's a very good question. I mean it's it's important as part of the normal immune hyun response for example immune response against a pathogen and it's important so that the immune response when it starts it doesn't keep going in an uncontrolled fashion her so it's actually an important molecule in controlling the severity of the immune response but cancer cells have worked out a way of expressing that to their advantage and obviously to the disadvantage of the patient sounds almost devious. That's just I. It is kind of devious. Okay so when you use a checkpoint inhibitor is it is it specifically targeted to help overcome the masking of the cancer cells specifically or the whole immune says yes so so. For example. One of the checkpoint molecules is a p. one and that inhibits molecule Akil on the immune cell called pd one so by giving an antibody that mosques of blocks that interaction then you don't have the cancer cells in addition of the immune cell and that allows the immune cells to attack. How often are we using? Immune therapy like with CIDER kinds right now. Not Very often with cytokines now. That was kind of the early phases. I think there is still a place for them and they are used in some situations. But that's it's not the common thing today. What did we do today? Today we have immune checkpoint inhibitors Like P. One inhibitors and there are other molecules to that are are important and other ones that are where antibodies are still in development but the PD wanted hitters for example for PD l.. One inhibitors Approved in a number of Kansas today. Then there are other ways. Of course that We can turn on the immune system will we can design the patient's own immune sells to specifically attack the cancer cells by manipulating the surface receptors. How do you do that? Well that brings us to the Tesol area. You have to identify a certain molecule on the cancer cells which is is relatively specific? Because you don't want to have that molecule expressed on vital organs for insurance or other vital tissues so it's at the moment that it's not amenable to old Kansas but once you've identified that you can Designer receptor to that molecule expressed on the surface of the cancer cell. And then you can introduce into the patient's own immune cells generally using a viral vector. You can put that the NFL encoding for that receptor into the T. cells DNA so that as the T. cells develop and And They've actually come to express that receptor which then specifically targets the Kansas. I feel like we need to walk through this step by step because it sounds like science fiction so So I you find molecule on the cancer. Did you think this is a molecule. We could attack where you think. It's on the cancer but not on vital organs then and how do you actually create Whatever the next step I mean visit like? How does it actually happen that we create something to attacker attached to that molecule? Walk you'll again. It's it's through knowing the sequence of the DNA sequence that encodes for these receptors than you can construct the that DNA a you can Also attached to that several other molecules that A not so much involved in the recognition of the cancer cells but in the activation and persistence of these Immune cells in the body and then you introduced that fragment of DNA through a viral viral vector that DNA integrate into the immune cells DNA. But how do we Let's even know the sequence. How do you actually like build build a molecule and then attached to it? I mean I imagine. There's not little construction sets that you'd like physically doing it. How do you actually build those things in the make them connect in the right order? Well I think that's that's the whole science of medical genetics. There are ways that you can actually Construct Day DNA with the sequence that you want. So you've now got this molecule. How do you attach these other? Molecules that your time medicine. Just you know how the naturally going to attach if you put them together or do you have to do something else. You officer choose these different molecules and you you know the sequences of these molecules and you can then attach these different sequences in i. I guess in in tandem so that when it's when the molecule is then Produced from the DNA or then it will be sort of like continuous molecule with Lincoln's in between that is expressed on the surface of the immune cell. And then usually there are signaling molecules. That I Also attached so at the end. You have some kind of solution that has a lot of this molecule in it more or less. Okay and then how do you get it to the virus. Like how do you then say. Okay now let's put these into specific viruses assist so there are certain viruses called retroviruses. That can actually integrate into the infected cells genome so these viruses You're attaching that piece of DNA the constructive DNA that of interest into the viral DNA. The viruses introduced first and then it integrates into the cells own DNA and then using the soles on machinery that DNA then is eventually translated translated into a protein That is Expressed ange suddenly the sequence of these proteins important because that allows the cell the the the molecule to be expressed on the surface of the cell as opposed to for example being destroyed within the cell itself so at the end you wind up with a t cell immune cell which is specifically created to go attach to the cancer cell and then signal that this sale should be killed. Yes so you have a receptor. That specifically targets the Immune Cell to the cancer cell and as I said You also attach the sequences. Ince's that allowed those immune cells to survive because if they don't live long enough in the recipient than the effect will not be Gerbil and also also There are ways to increase the activation of these cells once the immune cell recognizes the target cancer. So how does this work. It's actually been quite dramatic because it has you know. The early studies have obviously been performed in leukaemias and LYMPHOMAS and other cancers that are currently being investigated but really in a setting with the Cancer has been resistant to all non therapies. So this is a really hot population to treat so in in acute lymphoblastic leukemia. For example you'll getting remission rates rates of eight thousand ninety percent in lymphoma you'll getting remission rates that are probably in the fifty sixty percent in my Loma you'll getting responses The Not yet approved for my Lama. But you getting responses around the eighty percent mark and those are those are all numbers again specifically on patients nations that were otherwise incredibly hard to treat so that hi mark yes yes. So why are we not using this more and more. Well I think we will. I think We have to really go through the clinical trials Obviously the the early trials to demonstrate safety to demonstrate Not just the. There's a response but the ability of these responses And then really. The next step is to conduct trials earlier in the phases of the cancer and for example in multiple myeloma there are clinical trials ongoing at the moment in an earlier phase of the earlier phases of the disease and even comparing it to standard chemotherapy. That one would use to see which is really better. Is this hard to do. Is it expensive. The production of the COCKATIELS and manufacture of the actual treatment is is quite expensive. Yes why is it expensive is it is let me ask you this. Is this something that like a company is doing or is it every individual lab. That's doing this is there are a lot of obviously volved in in academic institutions. But but I think to be able to Export that technology in a very wide way. You really need to accompany. I don't think universities are you know would design for that. And really they'd taken up the technologists taken up by the companies and They're able all to Build manufacturing facilities And do this in a very broadway And of course you know. Many of them have are also doing their own. research and development in that area but each time. You're making a car T. therapy treatment. It is literally an individualized therapy like. It's only good for one person or is it good. For many people. Taking the the patient's own immune cells introducing these receptors into their own cell. So it is An individualized treatment but the the technology elegy for a given cancer. Is I when I pay my money and I get my cells back. That's for me. Full you only yes. Oh so okay. So how long does that. How long does that take the? The manufacturing process takes about two to three weeks. Okay is it intensive for the two to three weeks there's a lot of it you do some work in DC set for a while and then you take some steps and see it's for awhile. What we do is really collect? The patients on immune cells through the eighth Orissa's process which is similar to the collection of of stem cells. And then we these cells than shipped to the Company which manufactures it. It takes about two to three weeks to due to introduce the virus to expand the cells and then These cells out ship back and Lynnwood ready to treat the patient. We do it and what may when you say expensive. How expensive is well at the moment? for example COTY sell products Full fum patience around the three seventy five hundred one hundred thousand dollar mark that doesn't include of course the actual Other treatments that have to go along with the Infusion of cockatiels and of course it doesn't take into account dealing with some of the side effects of course so when we say those numbers of course sound very high to the general public. Is that something that we would expect to come down as we get better at mass producing this or is it. It really does take incredibly expensive technology. There'd be an it's likely to cost that much forever forever. Well I think there's a difference between cost and charge I'll surely and I think You know that's how much the charge is Sherman. I expect as You know maybe be more companies go into doing this as technology becomes more broad then I think probably the price will come down. I mean this sounds like it'd be a solution for lots lots of things not just cancer that if we could we can figure out ways the design One's own individual t cells to attack diseases. That could work with all kinds of diseases. This infections infections. Yeah yes so it. Is that where the future is. Do you think that's where the future is and I think they're already You know early research research going into that. I think the the you know cancer is just An obvious one CHIRP Kansas hot. It's treat than infections are. Are we using this for solid tumors as well as there are certainly This silly research going into that because there that again you have to identify target that is his specific or relatively specific to the cancer cell that is also not expressed on important issues. And I think that's really the difficulty in trying to apply that technology to Cancer Cells broadly because the antigens they expressed are also co shared by important tissues. What research are you working on right? Now where are your areas of interest. So we have a national trial open at Indiana University looking at the the Comparing chemotherapy versus coty cells. Multiple Myeloma There's also clinical trial that is about to open looking at My lawnmower homer in different phases of the disease including patients who have Essentially failed Most at least approved therapies. And obviously there's A. There's a big effort to be able to develop our own car T. cells PEPs directed against other malignancies for some of the things that we've described. FDA approval is it the now. Are these still third fourth line therapies whereas now that we like okay. Let's just go ahead and you. So it's approved route for example full Subtype of Lymphoma could call the few slots B. Cell Lymphoma and it's approved really in the setting where that lymphoma is is refractory to conventional chemotherapy. It's the approved currently for Pediatric Leukemia Acute lymphoblastic leukemia and in young adults up up to the age of twenty five again in the setting where the leukemia is refractory. I mean you're looking for new research and other areas is it that most of the focus right now is we need to find the target and then we can just go kart tea or is it. All the steps need to be worked out. I think both of those things because To apply lyod broadly to other cancers. It's really identifying a safe target But even with the Current on targets that we have in lymphoma and leukemia. It's really broadening the application to maybe early phases of the disease to Forgotten uh-huh leukemia extending approval to older patients with acute lymphoblastic leukemia. But there are also ways of Modifying defying the current technologies. So that Perhaps instead of one target you can use your design coty cells that have multiple targets doc. It's cockatiels that Can survive longer. coty cells that Maybe not generate as much Toxicity side effects. That was my next question. So what what what when someone receives Cartesian therapy sort of. How does that go? They get an infusion or multiple First you have to give chemotherapy. That is You know designed mostly to deplete the patient's own immune cells because if If you have a depletion of the patient's own immune cells you stop to develop. The body starts to produce a lot of side of kinds that will allow a proliferation of cells. So once you've depleted the patient cells then you can infuse the cockatiels and then you know leverage at that site a kind production to Get those coty cells to proliferate inside the body so that also is associated with drops in blood counts counts because that chemotherapy also affects normal he might appoint excels So they go through a side of peak phase where the council low Usually for a couple of weeks sometimes longer of course and then As these cells the Kathi cells proliferate they and start to actually attack the cancer cells. There's a lot of side kind. Production that produces produces an inflammatory response in the patient. So we call that cytokine release syndrome and that can manifest in in high fevers drops in blood pressure The reduced perfusion to important organ such as the kidneys and and so forth. So you need to support the patient through that cytokine storm And then there are the other main toxicity is Really development of neurotoxicity. That is less well understood but probably related to Cited kinds where patients can become. I'm confused they may have problems Speaking it's almost like Being having a stroke But in most cases it is reversible. And did you this once or do they have to go through multiple cycles of this. It's done wants Unless you can demonstrate that The the cady cells may be have not survived so there may be an opportunity If there's enough coty cells that have been produced To be able to give a second dose but generally speaking it's a it's a one off thing at the moment so we're looking towards the future. What what are you working on right now or what you see going that? You're most excited about. I'm most excited about about Seeing this seeing this application more broadly in because it's really restricted just to to very narrow indications at the moment I think being able to bring those coty cells earlier in the disease phase and more broadly and other cancers this will make a big difference to cancer patients in general and you see this happening in the near future I think so yes well for example in multiple Myeloma. I think of regular chance that we will have. If approval of Kati cells in this disease may be to twenty and then as the other clinical trials finish in the next year or two we may we see Broader application of the the currently existing coty cells in just other types of lymphoma and older age each groups with leukemia. And I'm sure within the next five years we will have coty sells That are targeting other cancers. I mean they already. The exist in very early phase clinical trials. I'm talking about potential approval for these other. Cancers can you tell us what types of cancers for example acute myeloid leukemia. Yeah now that's a difficult. Want to tag right it 'cause the Cadiz L. has the potential to also destroy normal. He might appoint excels because the the targets are not specific to the cancer cells themselves. There are some targets that are specifically expressed by certain sub types of leukemia. Where maybe the target is relatively more specific? I think that remains to be seen but it may be that. Do you have to combine these coty cells with the stem cell transplant. Because you may use the Kathi cells to eliminate the leukemia but in the process you might eliminate the patient's own normal matt choices so you then have to come in with A stem cell transplant to restore Humana opposes how many places in the country can do carty therapy at this point. I think it's very large and expanding I think The the centers mostly these centers. It is associated with Transplant programs And these centers have to be certified by the company They have to undergo some in training. They have to have the infrastructure to be able to Call collect the cells stole them in when they when they received by the company and and also be able to deal with the side effects that I mentioned These You know they can be more of an intensive care okay treatment that's required but is it like most big cities at this point so yes mo- most because this isn't just a couple of places now not not not all but most big cities so for example in Indiana You know we were the first at Indiana University There's the saint. Francis Group is starting also the program granted. They already have a transplant program in existence So there will be two places in Indiana Thank Indiana University School of medicine for their sponsorship. Their mission is to advance health. State of Indiana beyond by promoting innovation and excellence in education research and patient care

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