Chapters Transcript Video TIL Tomorrow and Further Uh, we've saved the best for last is what we say when we make one of our colleagues wait till the end to speak, but this is true today. Uh, one of the greatest, uh, pleasures of my career is to be working side by side and to host this meeting and to run the cutaneous program here at Angela's Clinic, Cedar Sinai with the Doctor Marker, and I won't say more because he'll show it to you. He's an amazing physician, surgeon, and speaker. Alright, thanks so much. I enjoyed the sessions and It give the audience a sense of relief that try not to, uh, too much more data, data out uh lots of information, lots of good information, uh, but I'll try and go back to the beginning in some ways and bring you up to speed a little bit in terms of where we stand with cellular therapies, T cell therapies, and so in terms of what I'll cover, what is a T cell? What are we even talking about? Uh, what does it do? How does it work? Uh, why are we interested in it? Um, how do we come to use T cells as a treatment? Why did it take so long to get here? And then how are we approving this therapy to move into the future. So, um, you know, basically we, we know and have known for a long time, the immune system has the ability to detect cancer, to recognize it as abnormal, and you attack it. So this is just a, a slide of biopsy the microscope of melanoma, just a melanoma in the skin, and melanoma cells are the big cells at the top, and all those little dark blue cells at the bottom are lymphocytes, many of which are T cells, and you can see a few of them are making their way up into the tumor, and they're not there by accident. And we actually didn't do anything to make them go there. They just went there on their own. Uh, on their own, they were able to recognize that there was something wrong with melanoma cells, and they are trying to deal with them. Uh, and so this has been known for a long time that this, uh, this happens, uh, and these immunotherapies about are ways in which this ability has been taken advantage. As as a form of treatment. Um, and so this goes way back so this William Bradford Foley, he's a surgeon in New York at the end of the 19th century, um, and he noted that occasionally a tumor might get infected, um, as a result of growing too much and then would spontaneously regress go away. So he cooked up, uh, literally cooked up uh mixtures of bacterial toxins. Uh, from various cultures and injected those into tumors. Uh, he knew that he had gotten the right dose. The patient developed a fever to 102 or 103, um, and actually saw quite a number of regressions of tumors that he injected. Um, but it wasn't very reproducible and at the time, it was, uh, it was a, a one shop, uh, sort of operation and was able to spread out to other locations away and, and what other cancer therapies came along sort of fell by the wayside. um but it has been maintained, this sort of idea has been maintained specifically innoma over the years, uh, really since the 70s and 80s and uh. My mentor Don Morton, uh, developed the concept of injecting uh something called PCG into melanomas. Uh, and we still occasionally do this, but this is similar to the TAC that you've heard about the RP1 you've heard about, uh, where we inject something into the tumor there, the hopes of making other tumors go away with that ejection. So this is just a case of a woman that we treated years ago who had um what what called intransit metastases. These are metastases of the skin and you can see she has hundreds of them on her leg, uh backside there and uh and so no way to operate on this, no regional chemotherapy for it. This was before the days of, uh, Uruguay and uh Keytruda and such. And so, uh, we injected a proportion of these uh tumors with ECG and you can see there was a patient that developed the sites of the tumors that we injected, and those tumors that we injected went away, um, but the rest of the tumors went away too, and so these uh spots that you see that are left there are just pigment tattoos basically, and all the melanoma was gone. Uh, so this really, even before we knew that much about the immune system through the concept. That we could harness the immune system to tumors. And so what's happened is there's been an explosion of effective therapies of melanoma. Uh, you could see through the 70s and 80s, uh, and into the 2000s, we had almost nothing to offer offer. And then there have been this raft of treatments that have come along. All the ones that are in the blue boxes are immune therapies and they are all dependent on T cells uh to work. How does all this, how does all this operate? So if you take a cell, any cell, uh, and look at how it works, how it functions, there's DNA in the nucleus that then produces mRNA, same things that are made of these vaccines, but the body does it on its own. The MRNA is then uh passed through a ribosome and are converted into proteins. Uh, and the one of the ways that the, uh, The body works uh to, to sort of maintain itself. These proteins are broken down, it's something called proteaso. The peptides and those peptide fragments are then loaded due to something called MHC or HLA. And so when you have this tissue typing done, when you look to see if you're eligible for some of these specific antibodies, those sorts of things, this is the specificity that's being looked at these immune cells, and these are really the context in which these peptides are presented. This is a way for the cell to say what's going on inside the cell. The importance of all of this is that is how T cells termmine. Whether a cell is a good cell or a bad cell. So the T cells then come into play. They come in, interact here and take a look at uh what peptides are being presented. So if there are mutations in the proteins, mutations in the DNA that lead to abnormal proteins, neo antigens, those get loaded in here. The T cells recognize that it's not a normal cell and know to kill it, and the T cell's job is to kill those cells. And so, uh, the way a lot of these therapies work is we manipulate this interaction in a way that enhances the ability of those T cells to kill the melanoma cells. There are those T cells that get so. Um, so in terms of immunotherapy, you have melanoma cells, T cells go find that, hopefully kill them, uh, that the dying cells potentially that release antigens that can be picked up by antigen presenting cells, immune cell, they can then mature dendritic cells that are very effective at stimulating and multiplying that immune response. Um, and we can impact that, that can be impacted by helper cells can be blunted regulatory cells. Um, and, uh, we now have these drugs we use that work through the system. So, uh, one of the drugs that you're familiar with is, uh, irrevoy or ripoliab, um, and that probably works at this interaction between antiscending cell, the cell that's supposed to, um, stimulate the T cell to go off and do what it's supposed to do, educate it basically, and there's an interaction between the antiroic cell T cell with. That activates that T cell, then goes off to find uh the melanoma cells that kill them. Um, and then eventually it circulates back around and may interact again with. So but now it has uh something called CTLA4 on it surface instead. And that interaction actually shuts that T cell off. It's the way the immune system normally turns itself off when it's clear, that sort of thing. Uh, but this can be used in setting out, uh, tumors tumors to escape. And so your voice is something that blocks that CTLA4 keeps that happen and it keeps those T cells on. That's sort of like a handbrake in a car. The other kind of break this system happens actually directly between the T cell and the melanoma cell, so more like foot pedal break, and here, those cells come into contact, um, with this interaction, the T cell potentially could kill that tumor cell, recognize it as animal, um, but it, it may have this PD1 on its surface that can interact. Potentially the PDL1 surfs the tumor cell and that interaction shuts that T cell off as well. And so thetrudas, pivos, um, they keep that from happening and allow those cells to continue on to to kill those, uh, those. Um, and so we have learned in this cycle of the tumor cells, the immune system, uh, how to manipulate uh the interactions. And so we can interact at the CTA 413, um, but it's not that simple even, um, there are ways of killing tumor cells to release more antigen more response. You can, uh, increase the maturation of deritic cells, various things that antigens. It can affect the other, um, regulators of the immune system. You can apply various cytokines and binding proteins and. Anyway, it gets a little complicated. Um, and for the simple-minded surgeon, it may be, you know, above my level. So, uh, we think about just using T cells, a fairly simple concept that just sending them in, sort of like a cruise missile, a fully packaged, uh, killing machines, and how can they, can we do that and it's this adoptive immunotherapy, uh T cell-based, uh, immunotherapy. And so this is a therapy that has been, uh, was pioneered by a guy named Steve Rosenberg, who's led the surgery branch at the NCR for many years. And just sort of emphasizing the incredible contributions to the MCI, the National Institutes of Health have made to cancer research over the years, uh, and so the idea of Rosenberg was that, uh, we know that these lymphocytes can infiltrate tumors in the body. You can surgically take those tumors out, um, and if you look at the tumors uh outside of the body, you can find those T cells that are in there again. But you can take some of that tumor tissue and actually put it into culture in the lab in conditions that favor the growth of the immune cells, uh, and those immune cells will grow up in the sculpture wells, kill the tumor that's in there, and then you can take those T cells, actually test them outside of the body and see if they kill the on the cells, um, outside of the body, and you can also expand them through a culture. Conditions called rapid expansion protocol to increase the numbers of many billions of cells and those cells then could be given back through an IV to patients with melano, uh, with the hopes that those uh T cells will be strengthened, numbers and ability, uh, so that they can then kill the cells that are in the patient. And that clearly works, uh, known it has worked for some time. Uh, these are just case examples that came from the SCI of tumors that, uh, shrink away, uh, often in fashion after its infusion of these cells, uh, but, uh, this is a fairly complicated treatment as you can imagine, and for many years it was only done at places like the National Cancer Institute or Anderson. Uh, places you need to Google Earth to be able to actually see the whole place. Um, and so it wasn't felt that it was gonna be practical to be used, uh, outside of those sorts of places. Uh, Doctor Ami and I were crazy enough to start our own, uh, till protocol uh years ago, and added to the growth lab and there's a cellular product that we made that we gave to, uh, a patient, um, but it was a pretty heavy lift, uh, and it wasn't going to be something that would be mainstream. Now it is mainstream, uh, and that is due to collaboration with commercial partners that have enabled, uh, the production of these cells in in a practical way. Uh, the first cells to the finish line for this were CAT cells used in lymphomas, leukemias. Um, and there are many companies that were involved in, uh, in developing those cAR T cells, uh, K cells, and then until the main focus here, uh, these tumor infiltrating lymphocytes, uh, that are grown in a bunch of companies that are working on that, uh, the ones that were first to the finish line in terms of approval of, uh, FDA approval for product. Uh, where Iovans and Adaptimmune, uh, both have FDFrovals now for their, uh, for their products, and then they're available now outside of a clinical trial. Um, the trial that, uh, uh, led to the approval of that till treatment for my advances was this one. you see Doctor meets the name there is second to the list, um, and the way the process works, from the patient's perspective, um, that there's a tumor that's taken out, it is cultured through this multi-step process in the lab. The culture process itself takes about 3 weeks, a little over 3 weeks. Uh, from the patient's perspective, um, they have the tumor removed, uh, surgically removed, and then this period where they're waiting and that process goes on, it's actually probably more like, uh, uh, 5 or 6 weeks, uh, typically it takes between, uh, the time when the cells, tumor is taken out and the back, uh, because there are quality control things that need to and other things that delay the, um, the treatment itself. And when the patients get the cells, they have uh been recently treated with a lympho depletion. It's chemotherapy that's designed to get rid of the lymphocytes that they have in circulation already and essentially create space uh for the lymphocytes that they're about to be infused, and then they get this interleukin 2, that cytokine that you've heard about that's a lymphocyte growth factor that supports those cells after they. Uh And this is that waterfall plot. It's maybe the only plot that I have for you guys, uh, that shows uh these downward uh bars, and that represents shrinkage of the tumor, and you can see that the vast majority of the patients there was some tumor. Um, the patients that experienced responses, those responses most of the time were durable, so lasted for over 2 years at this level of follow-up, um, so it seemed like this one time, uh, once and done sort of treatment, uh, did have a lasting benefit for the patients that responded well. And so it had approval uh last year. There are a lot of challenges with this therapy though. It is not for everyone. Um, there is the delay in terms of timing, uh, the, uh, the tumor is harvested and then when they actually get the treatment, you need to have surgery to get the tumor out, uh, you need to balance the risk of a procedure for removing the tumor tumor, uh, with being able to get a sufficient sample to be able to create the therapy. There's toxicity associated with chemotherapy. They get preparation. And there's toxicity that's associated with that IL too uh to support this cells afterward, and then it doesn't work for everyone we get cells uh for people, doesn't cause the tumors to go away for all those patients for a variety of reasons, uh, and, uh, and so those are the areas, all of these areas are areas that work being done to try to approve the therapy, uh, to make it available and effective for people. Um, just an example of a patient that we treated in terms of the surgical, um, planning, uh, for this and selecting the appropriate tumor patient had a lot of different pre therapies, going to get, uh, till, a tumor, very small tumor, liver, big tumor in adrenal gland, and then another small tumor just in the soft tissue. So for this setting. Small soft tissue leash is clearly the right one to get to without causing a lot of uh toxicity from the surgery itself, uh, but providing a sufficient uh samples. So how are we altering these regimens to try to improve the therapy. You can step up the timing, moving it earlier, have more time to get there, potentially reduce the intensity of some of these. Uh, conditioning regimens, selecting better lymphocytes from the tumor to potentially use, uh, combining these therapies with their effective, uh, uh, interventions we have, one blockade, uh, other novel interventions, uh, and then delivering tumors. The cells in different ways, and then modifying the till cells to try to make them more effective and show you some examples of how that work. One is with altering the T cell receptor, the thing that makes the T cell able to identify a very, very specific target, um, and T cell receptor. And so there are a couple ways of doing that. Uh, one is by uh taking out peripheral blood lymphocytes. And those lymphocytes then can be altered. You can introduce genes into those cells that change from one T cell receptor receptor to another 11 that we know is very specific for melanoma target. Uh, so these are transgen T cell receptors. The other way is with these R T cells, Maric antigen receptor T cells, where a gene is introduced into these cells, makes them put on their surface what is essentially like an antibody, uh, but it is linked to the same T cell signal with. So receptor. And so then these modified things can come up against either the peptide in this MHC just like normal T cell kind of interaction, or by red cell surface protein through this antibody type uh molecule. And these different approaches have pros and cons to them about what the target can be, those sorts of things, um, and so both approaches may have, uh, have value. Uh, the other thing that can be done is altering the function of these T cells. So this is just the standard till that is the till that I've been selected because we already know they make their way into tumors. They have the right T cell receptors to do that already, but, uh, instead of relying on exogenous leukin 2, that cytokine that has all the toxicity, uh, to bind receptors, um, these cells, these are the LBX 115 cells that Doctor Memmi mentioned. Have a gene introduced so that they have membrane bound IL-15 at T cell stimulated cytokine on their surface, and then they can be given this small molecule drug that activates that essentially an on switch for that, and the cells stimulate themselves, you don't have to give the I to, so this may be a way of avoiding that toxicity. There are lots of potential immunologic hurdles to get over uh with immunosuppressive environments and uh antigen escape and those sorts of things, and there are ways of modifying these uh T cell receptors American antigen receptors or T cell receptors to try to overcome those difficulties. And then a separate type of cell that can be used as a cellular therapy and K cells, these killer cells that may have inherent ability to recognize and contain cancer cells. So, Uh, overall, it's, uh, clear now to us, uh, T cells are critical components of immuno therapies, these adoptive immunotherapies, but also the checkpoint immunotherapies. You heard about the ET T cells, uh, to be work for any of those to work. There are still challenges that applying to therapy uh to patients more broadly, uh, that we are working uh with ongoing research to try to overcome, to try and make these cell cell therapies available to as many patients. Uh, and this, as you can imagine, is an enormous team effort. So the till therapy is very complicated and requires a bunch of people with a bunch of different types of expertise. This is the, uh, Angela's clinic, uh, group, uh, with nurses and uh medical assistants, and, uh, pharmacists and many, many others who make all this come together, uh, or. So, I appreciate the opportunity to participate in this posing again. Created by Related Presenters Mark Faries, MD Co-Director, Melanoma Research Program View full profile
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