is really broad. I have a huge list here, right? Checkpoint inhibitors, Keytruda, Pembro, Nivolumab, we're all using it. Oncolytic viruses, cancer vaccines, monoclonal antibodies, cytokines, immunomodulators. It's a whole new world out there. But I really did want to just explain to you T-cell transfer therapy, because it's so fascinating. And we actually have trials of this in ovarian cancer, and it's a complicated topic. So Susan, I'll take the next slide. Thanks. OK. So adoptive cell therapy, remember I showed you the whole list, is really T-cell transfer therapy. And it concentrates on T-cells given to a patient to help fight the body, such as cancer. And within this smaller category, remember that I had this huge list, we have peripheral autologous T-cell, NK cell therapy, not used very often. And then there's TIL, tumor infiltrating lymphocyte. And there's a big trial at MD Anderson for cervical cancer that I'll tell you about. And then chimeric antigen receptor T-cell, or CAR-T. It's really in vogue with all our medical oncologists. It's very important for the hematologic cancers. Next slide, Susan. Thank you. So CAR-T stands for chimeric antigen receptor T-cell therapy. Next slide. What are CAR-T cells? They're actually T-cells that have been engineered to be like super T-cells. They have receptors that bind to a specific, one or two specific antigens on the cancer cell. And so what makes them all different is that people are analyzing the cancer cells and saying, what exactly is the receptor on, sorry, the antigen or the protein on the cancer cell that is gonna make this T-cell stick? So it's actually very proprietary. People are finding it out, engineering these T-cells. I kind of think of them like super T-cells. Once they bind, they really almost never unbind. Next slide. Okay, and let's go to the next one. All right, what are the current indications for CAR-T treatment? All of them are hematologic malignancies, very effective. And then recently lupus, I think melanoma came out recently but none of the solid tumors. So any research we do in a solid tumor is pretty new. Our medical oncologists have a lot of experience with the heme malignancy. So we're glad that it works. We really want this to work for our ovarian or cervix cancer, right? Next slide. Okay, so a little bit complicated but I wanna explain how this works and then you'll see kind of how interesting it is. So first we collect the patient's own white blood cells. We're pulling out the T-cells. You can see that in the first slide over there. I don't know, does this pointer work, Suze? Can you see the pointer? Yes, go slow, we can see it. All right, then we pull them out and then we do genetic engineering. And this is really, it takes like four to six weeks and we, it's several, we can insert a virus, we can insert mRNA, but we change these T-cells so they recognize these very specific antigens on the cancer. I will say at UNC, we think we're really hot. We have this BH7-3 antigen on the cancer cell. And then we're developing our own CAR T-cells that recognize that. And we think this is the, you know, like the thing to treat patients with. Other institutions have their own antigen combination. So here we have the engineered CAR T-cells and they're being engineered and then we expand, meaning grow them, right? We're then going to infuse them back in the patient and see if it works. And you get one shot at this and you only get one shot. And also, next slide. We have to lymphodeplete these patients. So this is why as GYN oncologists, we're never going to do this by ourselves. We need the bone marrow medical oncologists. They give these high doses of Cytoxan and Fluderibine and lymphodepletion means we're really lymphodepleting. We're wiping out their endogenous cells. And this is so that when we re-infuse these cells, they're more effective. But think about it. This is a little bit scary, right? There's a lot of complications that can ensue. Next slide. So here's the schema of what we did. Remember we said apheresis. We took out the cells. Takes like six weeks to grow these. In the meanwhile, we can give some chemotherapy to tide our patient over, but eventually they're going to be admitted for lymphodepletion. And then we're going to give back these engineered T-cells and hope that they can recognize and kill the cancer cells. It's so intense. The patients have to guarantee that they're going to stay within the proximity of the treatment institution for 30 days. It is a huge undertaking. And I'm going to show you some of these side effects in a minute. Next slide. These are two very specific toxicities and patients can die. One is cytokine release syndrome. Happens usually in the first week, ranging from low grade to high grade symptoms. Multi-organ system failure really can be toxic. And it's nothing we see with our regular chemotherapy. The second well-known toxicity is ICANS, a neurotoxic syndrome. Usually in the second week, patients have strokes, neurologic delirium, other all neurologic symptoms. And again, patients can die. So these are pretty serious. And again, as a GYN oncologist, you're always working with your medical oncologist. But what's really neat is the next slide. So patients used to risk all of this. What is now built into these cells is a suicide switch. Believe it or not, if these symptoms start to appear, you can give these patients a pill. Here it is. I can't even say it, remidacin. And it will turn off the effect of the CAR-T and resuscitate these patients within 24 hours. Isn't that amazing? So for the patients who really look like they're going downhill, first of all, you can give them the CAR-T, hope it works, but you can resuscitate and essentially save them. I mean, I think this is just a phenomenon of genetic manipulation of these T cells. And it crosses the blood-brain barrier. Perfect. Next slide. So what's the difficulty about this CAR-T? Shouldn't we do it on everyone? You know, I showed you, it's a long time, takes a long time to engineer. It's almost 700,000 to a million per cycle, right? So all of these are clinical trials, or I guess funded by insurance for the heme malignancies. Very complex, right? I showed you, there's us, there's the medical oncologist, there's a whole staff of nurses watching out, and then the 30 days afterwards. As I said, patient hardship, they kind of need insurance. You know, if you don't have money, it's really hard to do this. And you have to find the right antigen. What is the magical antigen for ovarian cancer? As I said, at UNC, we're working on B7H3. They're trying to patent it. They think it's going to work. You need to find a cancer cell protein that is specific to ovarian cancer, but not expressed on much else, right? Think about it. If it was on every other cell, your skin cell, your heart cell, then those would get knocked off too. So really difficult. All right, so that's CAR T. Next slide. Oh, so the reason I know a lot about this is we have one of the clinical trials in the whole country where we're giving this intraperitoneally. It's the phase one. We had a partial response on one, but as you know, with the phase one, that's not the purpose of it. All of our patients have been fine, and we're just going to continue with this. We now have a suicide switch built into this B7H3. So we'll hopefully have some results one day. Takes a long time, and it takes a long time to accumulate patients who want to be on this phase one. Very complicated. Next slide. So I'm going to switch gears and talk about this other very popular T cell transfer approach. And they have this, you know, if you have a cervical cancer patient, this is ongoing at MD Anderson for cervix cancer. It's called TILT therapy, tumor infiltrating lymphocyte. Really similar to what I just described. Next slide. So again, let's see. I read two of these. Tumor infiltrating lymphocytes harvested. So we got them from the tumor, but not from the IV, not from the systemic system this time. They're grown, as I said. Patients get lympho depleted, and then you infuse these cells back in, but they're nonspecific. So as CAR T, remember I said, we are trying to make them custom cells binding to one or two targets. These are just nonspecific. They're just binding, kind of going out as a big old army and stimulating lymphocytes and seeing if they can take. So in a way, this is a little cheaper. It doesn't take as long to grow because you're not engineering these cells. They're just kind of diffusely throwing them back in. And so far I've sent two patients to MD Anderson for this, and their cancer has disappeared. So I will wait to hear what they have to say with the TILT cervical cancer, but I just want to let you know, CAR T and TILT are the most relevant adoptive T cell therapies for our cancers. Next slide. Clinical use, as I mentioned, the cervical clinical trial. And then I think O'Malley reported 40% response rate. And then when you add Pembroke for maintenance, the response rate is 50%. And a meta-analysis recently for GYN cancers, hard to do because there aren't very many good studies, but they suggested a 2.6 fold increase in response rate. So again, I think this is the way of the future. The CAR T, expensive and not quite there, but TILT seems quite doable. Next slide. Difficulties, as I said, complexity and cost. All right. And then my last slide here. This is a new trial. Let's see, I think everyone knows Ronnie Alvarez. It's Ronnie on here, Coleman, the usual group. T-Vigil is coming out as a GOG trial. This is really interesting. They're going to ask you to obtain tumor specimen. They're gonna engineer it. And it's gonna be coming back as a autologous vaccine, a sub-Q injection every three weeks. Now, isn't that easy? No lympho depletion. And they've already had a phase two, showed a, I think PFS was good. Anyways, this is coming out soon for all of us to access, for all of our patients, right? Easy. All right. I think that's my last one. Yes. So again, a mini lecture just on adoptive T cell, but I wanted to explain to you what CAR T was about, what TIL was about, and the autologous vaccine that was coming.

T-cell transfer therapy

CAR-T therapy

TILT therapy

cytokine release syndrome

neurotoxic syndrome