Melanie Cole, MS (Host): CAR T-cell therapy, repurposing cancer therapy for myasthenia gravis. We're learning about this innovative treatment, altering patient's T-cells to fight disease today on AHN Med Talks, an informative resource for physicians across various specialties as we delve into the latest medical insights and best practices, ensuring you stay at the forefront of your field.

I'm Melanie Cole. And joining me today is Dr. George Small. He's a neurologist and Director of the Electromyography and Nerve Conduction Laboratory at Allegheny General Hospital. Dr. Small, it's such a pleasure to have you join us today. I'd like you to start by telling us about CAR T-cell therapy as one of the most fascinating course of adaptive immunity. How have cell therapies such as CAR T changed the landscape of cancer treatments? Give us a little bit of an overview of what CAR T-cell therapy really is.

George Small, MD: It actually came to my attention through the cancer physicians at Allegheny General Hospital and Allegheny Health System. I was not much schooled on this particular therapy until I received an invitation to be part of a study to alter an individual's own white blood cells to potentially cure them of the autoimmune disease, myasthenia gravis, or at least improve their quality of life outside of other therapies that are well known to work and the many newer therapies that are available.

Melanie Cole, MS: Well, then how does the mechanism of CAR T therapy align with the pathophysiology of myasthenia gravis? Give us the connection there and why this is even being looked at.

George Small, MD: Like a lot of autoimmune diseases such as rheumatoid arthritis or lupus and even some cancers, whose origin likely has to do with a disordered immune system rather than a pure cancer issue, myasthenia gravis occurs when people produce autoantibodies, when those antibodies that are usually destined to kill bacteria or viruses are directed against one's own body tissue. In myasthenia gravis in particular, the bad antibodies will attack the nerve and muscle junction, preventing nerves from communicating with muscle and causing patients to be weak. In any event, lymphocytes, which are divided into B and T-cells, have been targeted for years by the cancer people by trying to deplete them to prevent people from having leukemias and lymphomas that are deadly.

It has come to my attention just recently that one of the standards of care now is to offer people CAR T therapy, where their own white blood cells are harvested through a plasmapheresis machine. Those cells are frozen. They are sent off to a manufacturer who actually changes the DNA or RNA of that T-cell. The patient then receives those cells back through an infusion, and they essentially command the immune system of that individual not to make the pathogenic antibody. This is done, as I mentioned, as a standard of care for certain types of leukemia and lymphomas to put them into permanent remission. And as far as I know, this is one of the first general autoimmune diseases in which CAR T therapy is being studied for myasthenia gravis in particular.

Melanie Cole, MS: Isn't this fascinating and how fast this field of CAR T-cell therapy is moving and adapting, and no pun intended, but adapting for real. Now, clinical trials, tell us about any that are ongoing. The KYV-101 study, what is that?

George Small, MD: If you're referring to the KYVERNA trial, that is a trial which is going through our institutional review board that I would like to be part of. I was invited to be part of that. And that trial is actually similar to many of the cancer trials. If I could digress for a moment, I've already enrolled a patient in a different CAR T trial that involved T-cells, but involved altering the messenger RNA of T-cells. That is not generally done or used in patients with cancer, but the KYVERNA trial, which I believe you are talking about, does use the same technology that is used for patients with leukemia and lymphomas because in particular it alters the DNA of the T-cells.

The trial I was fortunate enough to be invited to be in and enrolled a patient in involved a study with RNA altered T-cells that was much safer than the KYVERNA trial, which involves the standard way of altering DNA of T-cells. Now, in cancers, DNA is altered in T-cells and patients can have a very deleterious reaction to those CAR T-cells, causing in a sense an allergic reaction. So, those patients have to be admitted to a hospital for 10 days in a mandatory fashion when treated for cancer or in this KYVERNA trial that you're mentioning. That was not the case in the mRNA-directed Descartes trial, which we completed already. As much as I may have sounded like a downer in the fact that patients can get in a sense what's called a cytokine release syndrome, in a sense think of it as an allergic reaction to the CAR T-cells, that usually does not happen in RNA altered T-cells, but does in DNA altered T-cells.

At our flagship cancer hospital in Pittsburgh associated with AHN, West Penn Hospital, Dr. John Lister has used CAR T-cells altered by DNA to put certain lymphomas and leukemias into remission. The KYVERNA trial that you're mentioning will also use that particular method in myasthenia gravis patients, and that trial has to pass muster in order for us to enroll patients in it. And I was very, very happy and honored to be invited to be in that trial.

Also, the previous trial where mRNA is altered, which really has a lower chance of that allergic or cytokine release syndrome. Now, patients with untreatable or poorly treatable cancers are usually willing to be part of such trials with the DNA therapy. In fact, there's almost an on-call group of oncologists at our West Penn Hospital that are called in in case patients get the reaction I mentioned to with the cancer patients I mentioned. They were also at the ready in this mRNA trial we already completed, but very few patients in that trial would get the cytokine release syndrome. Our patient in it had no negative reaction and was not expected to. In the KYVERNA trial, many safeguards are put in place since the DNA of the T-cell is altered. And I can go into details as to why that can be very effective in autoimmune diseases and cancer, but also carry some risks.

Melanie Cole, MS: I would love for you to do that, and I'd love for you to expand a little on how you might anticipate and manage the cytokine release syndrome and other immune-mediated toxicities because those things, those challenges are some of the main that you're going to be jumping over. So, speak about that and expand on that as well.

George Small, MD: Under the auspices of our cancer hospital and the care of Dr. John Lister and the team of hematologists there, they have done many CAR T trials in cancer. And we joined them in the trial that I had mentioned that involved mRNA therapy, where they had oncologists at the ready to be called in an emergency, if those side effects or cytokine release storm occur. That will also occur, and is necessary to occur, in order for the trial you mentioned to be approved through our Institutional Review Board. And Dr. Lister and other individuals I've worked with for years at West Penn Hospital are at the ready and have a standard method of treating patients with that cytokine release syndrome.

The big difference between treating patients with the DNA-related CAR T therapy versus the RNA is that the patients with the DNA-related therapy actually need to have their bone marrow cleared of white blood cells. In other words, they have to get chemotherapy as if they're going to have a bone marrow transplant. And in that case, the mandatory 10-day stay in the hospital is entertained so that we can be ready for their cytokine release syndrome. There's a whole panel of tests and a whole panel of safeguards involved in helping to prevent side effects in those patients and the cancer physicians who are well versed in this. And the nurses and the team of people of support staff in the medical short stay center there are at the ready to do that. So in a way, I'm very fortunate in being invited to be in the DNA CAR T trial to have people at the ready and available, and we've already discussed that so that we can be part of this trial.

Melanie Cole, MS: Dr. Small, since we know there's an immunosuppressive impact of CAR T on patients and myasthenia gravis patients already have compromised immune function, how do you foresee this therapy impacting the long-term management of these patients? Take us from bench to bedside here, particularly for patients that are refractory to other treatments.

George Small, MD: Absolutely. I think that any individual who turns on a television show these days sees therapeutic advertisements for myasthenia gravis, they just can't be avoided. There are many newer therapies. Many of these new therapies do have potential side effects of causing very dangerous immunosuppression. Although these therapies that we've used extensively, we must have used these therapies in 40 different patients with myasthenia gravis over the last two years. And these therapies help people spare themselves some of the toxicities of steroids. My mantra in treating patients with myasthenia gravis in general is that I want to avoid steroids as much as possible.

Now, that is heresy. Steroids are the mainstay of treatment in myasthenia gravis. Short term, they save lives. Long term, they increase death rate and mortality from obesity and from other side effects and hypertension and kidney disease. If we could get any therapy into a patient that manages their myasthenia gravis well without the side effects of steroids, we're doing patients a favor. And in particular, with CAR T therapy, there is actually a chance of putting their MG into remission. We cannot put a patient's MG into remission now with any of the therapies that are available. Generally, it's a meet and treat operation. We have a patient with myasthenia gravis who may not be able to swallow or breathe. We treat them with a medication, and then they repeatedly get treated with it. With CAR T therapy, there is a chance of putting their disease into remission. I really like to avoid the word cure. But certainly, a long-term remission is possible just as the long-term remission is possible in the lymphomas and leukemias treated with CAR T therapy themselves. I know that other people are champing at the bit in the Rheumatology world and in the Allergy and Immunology world to apply this therapy to their diseases.

Melanie Cole, MS: That certainly is true. So wrap it up for us, Dr. Small, if you would. This is fascinating, and it's such an interesting and exciting subject and an exciting time in your field. As you look into these studies and these clinical trials, what would you like other providers to know about CAR T therapy for myasthenia gravis, the work that you're doing at Allegheny Health Network, and the key takeaways, the most important messages you'd like them to take from this podcast?

George Small, MD: I think when a very busy primary care physician or internist or a rheumatologist or endocrinologist hears about Myasthenia Gravis, there are so few patients with myasthenia gravis in the country, perhaps 50,000, it's known as an orphan disease. It is not an orphan disease in the city of Pittsburgh, given our large contingent of patients, given the association with the National Myasthenia Gravis Foundation that I have, and my partner in neuromuscular disease, Dr. Rana has, so that we can be used as a referral base for any individuals interested in potentially approaching CAR T therapy for their myasthenia gravis patients. That way, if a patient has myasthenia gravis is seen by a colleague in the general field of medicine, they can be referred to us directly for not only the traditional treatments or some of the newer treatments that are available that are steroid-sparing, but also for the potentially, I dare say it, curing of myasthenia gravis or the remission chance of putting people into a disease state that's very minimal with this therapy. In other words, refer the patients to Dr. Rana and myself at Allegheny Health Network.

And I might add, if you don't mind, we already are a wonderful referral base, even from the central Pennsylvania area, the Northern and Southern Pennsylvania area, and we're known for this. And this is because of the hard work of many of the members of our staff, nurses, the medical short stay unit at West Penn, and the Oncology and hematology team all throughout the AHN system.

Melanie Cole, MS: It certainly is a comprehensive multidisciplinary approach. Dr. Small, thank you so much for joining us today. And to learn more or to refer a patient, please call 844-MD-REFER or visit ahn.org. Thank you so much for listening to this edition of AHN MedTalks with the Allegheny Health Network. Please always remember to subscribe, rate, and review AHN MedTalks on Apple Podcasts, Spotify, iHeart, and Pandora. Until next time, I'm Melanie Cole. Thanks so much for joining us today.