Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And we have a thought leader panel for you today highlighting the Myositis Clinic at Northwestern Medicine and our cellular therapies roundtable. In this panel, our Dr. George Georges, he's a Professor of Medicine in the Division of Hematology Oncology, and he leads the Stem Cell Transplant and Cell Therapy for Autoimmune Diseases Program at Northwestern Medicine. Dr. Georges will be moderating today's discussion. Joining Dr. Georges is Dr. Christine Hsieh, she's an Assistant Professor of Medicine in the Division of Rheumatology and co-leader of the Myositis Clinic at Northwestern Medicine; and Dr. Arjun Seth, he's an Assistant Professor of Neurology in the Division of Neuromuscular Disease, and he's co-leader of the Myositis Clinic at Northwestern Medicine. Dr. Georges, I turn it over to you.

George Georges, MD (Moderator): Thanks, Melanie. Well, we're here today with my colleagues, Dr. Christine Hsieh and Dr. Arjun Seth. And we're going to talk about cellular therapies and myositis. Dr. Hsieh, can you briefly describe the Northwestern's Myositis Program?

Christine Hsieh, MD: Sure, Dr. George. So, we created this program about three years ago in conjunction with Dr. Seth and the neurology department to really meet this unmet need for this rare condition. Inflammatory myopathies are quite difficult to diagnose and often affect more than just the muscles. So oftentimes, there can be skin, lung, joint, esophageal involvement. And so, it can often be difficult to make a diagnosis correctly and come up with an adequate treatment plan. So, we started this program, and we meet once a month in the neurology department where the patients come in and they see both a neurologist and a rheumatologist on the same day.

In addition to seeing both of us, we also have a cardiologist, a pulmonologist, a speech therapist, a respiratory therapist, other ancillary staff that are there to evaluate the patients on site. This helps the patients for two reasons. One is often most of these patients come from very far away and having to come in and do multiple appointments of specialists and therapists, all on different days of the week. It can be really hard for them. So by seeing them all together, we can really coordinate care and help them logistically combine their appointments together.

Secondly, we can offer them clinical trial opportunities. So, we evaluate the patients, and we have a registry that we can offer them to enroll in. That really helps us to learn more about the inflammatory myopathies, how the natural progression is, what treatments are most optimal for them. And also, in patients who are candidates, we can offer them cutting-edge clinical trials such as CAR T therapy or other therapies that are on the horizon.

George Georges, MD (Moderator): I can really see how This is just a wonderful model and an excellent opportunity for patients who have these rare diseases, difficult diseases, to be able like one stop and get all of the treatment that they need and assessments.

Christine Hsieh, MD: Yes. Yeah, it really can be helpful for them. Most of these patients suffer from profound weakness, so just even physically getting around can be challenging for them. So, imagine having to navigate a hospital system, coming down multiple times a week, seeing multiple specialists. Most of these patients see at least three to four specialists.

Arjun Seth, MD : That's a lot. It is nice actually. The collaboration's been excellent. You know, when we had this vision of creating this program three years ago, it was really nice to be able to collaborate with Chrissy and actually build this program together and have sort of support from our department of neurology to really build it out with the subspecialists already kind of in the clinic and the ancillary staff there. And we try and coordinate things like their EMG, nerve conduction studies the same-day, so we can kind of do all the diagnostic workup then and there to help manage patients.

George Georges, MD (Moderator): From a neurology perspective, what do you think are the biggest challenges in diagnosing and managing patients?

Arjun Seth, MD : Great question. I think some of the biggest challenges with this is, one, identifying the problem first and really making sure that someone has myositis to begin with. So, I think having combined rheumatologists like Dr. Hsieh and then a neurologist actually evaluating patients, first and foremost, really make sure that nothing else is being missed. Sometimes there are genetic muscle diseases that get misdiagnosed as myositis and they just have a genetic muscle disease, or patients have inclusion body myositis so with, you know, sort of distal hand weakness and quadriceps weakness and given a diagnosis of polymyositis, and they really don't have that and have been on immunosuppressants. So, we take a step back, reevaluate, and then rediagnose at that stage.

George Georges, MD (Moderator): That makes a lot of sense. It can be super challenging, really. These are complex diagnoses, multifactorial, and also rare. So, it's oftentimes difficult to sort it out.

Arjun Seth, MD : Yeah. That's right.

George Georges, MD (Moderator): Dr. Hsieh, what are the standard treatment options for myositis? And where do you think they fall short or where are they inadequate?

Christine Hsieh, MD: Yeah. So, the standard treatment options for myositis really are extrapolated from other autoimmune conditions like rheumatoid arthritis and lupus. We really don't have any great large-scale randomized controlled trials, which are the gold standard for treatment in myositis.

The one major one with rituximab phase III controlled trial actually failed its primary outcome, although there is a suggestion about two-thirds of patients responded in that. So, we still use things like rituximab off-label, but that really was the only major randomized phase III controlled trial up until recently. So, most of the treatments involve steroids or IVIg upfront. So, IVIg and steroids can decrease the inflammation and symptoms immediately, but oftentimes they can have long-term side effects that are really problematic, especially with the steroids. So oftentimes, we start steroid-sparing agents pretty immediately. So, those can include things like methotrexate, azathioprine, mycophenolate, tacrolimus, cyclosporine.

So, we tend to start those, again with mainly information based on expert consensus and case series. And if they fail that, then we're usually trying things like rituximab, or even more recently, JAK inhibitors off-label, such as Xeljanz or Rinvoq. So, most of what we have is not really based on great data. So, sometimes we're kind of shooting in the dark with trying to figure out what the best treatment options are for these patients.

George Georges, MD (Moderator): Trying to make the best of what you can with the options that are available.

Christine Hsieh, MD: Yeah, exactly.

George Georges, MD (Moderator): Dr. Seth, how do you manage refractory cases when these more conventional therapies fail? This can be particularly challenging for patients.

Arjun Seth, MD : Yeah, it can be very challenging. We've had multiple patients who have failed sort of one or two first steps or second steps in terms of their therapies. We actually do additive therapies where patients have to be on four or five different therapies to try and control their muscle inflammation, unfortunately. And that's really what plays into why part of the reason that we wanted to start this program was to really be able to offer clinical trials to patients for really refractory disease. And we started up a clinical trial. It's been doing pretty well thus far with an Fc receptor antagonist with very promising early results. So, we're hopeful for that sometime next year to have phase III data with that.

George Georges, MD (Moderator): That's really encouraging. You know, it's great. But I can still imagine certain scenarios where there may be toxicities from some of the prolonged immunosuppression, as you mentioned, especially with the steroids or toxicities or intolerable side effects from some of the other medications can make it particularly challenging to sort of solve the problem of the inflammation.

So, we've talked a little bit about some of the conventional therapies or the current available therapies. I think I wanted to maybe shift to talking about the cellular therapies and what's currently happening here at Northwestern. And maybe to start that off, I can talk about the cellular therapy program for autoimmune disease. I've come recently to Northwestern from Fred Hutchinson Cancer Center in Seattle. And I'm particularly interested in applying the knowledge that has been gained in the hematology oncology fields for treating patients with lymphoma or hematologic malignancies and trying to apply that knowledge to patients with severe autoimmune disease. We've used autologous stem cell transplantation, hematopoietic stem cell transplantation as a treatment for some other autoimmune diseases such as scleroderma, systemic sclerosis.

But recently, really, we've applied the chimeric antigen receptor T-cell therapy, genetically modified T cells, CAR T-cells for short-- nothing to do with an automobile. It's just sort of a genetically modified T-cell to do what you want it, engineer it to do what you want it to do in patients and trying it in severe autoimmune disease. And I would say that the preliminary results or the initial results that have been reported in the New England Journal of Medicine and other peer-reviewed publications have been very promising. And there's been a strong interest in maybe exploring the use of these genetically modified T-cell therapy using the patient's own cells, the patient's own T cells that are genetically modified in the laboratory, and then reinfused back into the patient, the patient's own cells back to where they came from to eliminate B cells, to eliminate the component of the immune system that might be triggering or exacerbating the autoimmune disease.

And so, we have three trials now at Northwestern for patients with myositis with CAR T-cells. I would say that, you know, we're still in the early days and we are still trying to learn how to optimally use the cells. I think that I've worked with both of you on trying to find patients that are suitable candidates for this study. Dr. Hsieh, what are some of the challenges that you think have come up with thinking about CAR T-cell therapy for patients?

Christine Hsieh, MD: Well, I think part of the challenge with these CAR T-cells is that inflammatory myopathies often involve many organ systems. And so, sometimes there's one organ system like the lungs or the skin or the muscle that are disproportionately active compared to others. So, the real challenge for these trials is that they do have to have muscle inflammation and muscle involvement and evidence of muscle weakness on exam. And although some of these patients can still have active organ manifestations of it, if their muscles aren't active, they may not qualify for these trials. So, that can be one of the challenges. I mean, also just, you know, time for many of these patients, they do come from far away. And so, being down and coming here frequently and being here for an extended period of time can be challenging for them too, and having the social network and support for it.

George Georges, MD (Moderator): It is a real-time commitment, isn't it?

Arjun Seth, MD : Yes.

George Georges, MD (Moderator): For sure.

Christine Hsieh, MD: Yeah.

George Georges, MD (Moderator): I would say that another thing to consider though is that for patients who have severe myositis, you really want to consider some paradigm-altering therapy, really. Because, certainly, the prednisone or high-dose steroids really can cause so many other severe adverse long-term effects, infection, complications, bone demineralization, osteonecrosis, all sorts of almost innumerable complications that can occur. And in patients who have severe myositis, it would be appropriate to try something a little bit newer and maybe a little bit potentially risky, but that could maybe really stop the autoimmune disease process.

And to think that the three trials that we've opened here have slightly different inclusion criteria, minor differences in inclusion criteria for patients. So, we can find a study for most patients. But you're right. Lungs have to be well enough, not too ill. The heart function has to be adequate, not too ill, right? And patients have to be weak, but not too weak, there still has to be some residual inflammatory muscle function. And so, that's a little bit of a challenge, catching the patient at the right time in their disease course for this therapy.

Maybe I'll take an opportunity to kind of just explain or walk through what would happen with the CAR T-cells. Generally, patients undergo a screening period, really, where we have about-- within a week or two, we can do all of the necessary screening tests, evaluate lung function, cardiac function, renal function, liver function, make sure the vital organs are well enough to tolerate the upcoming therapy. And then, if we use the autologous CAR T-cells, autologous meaning your own CAR T-cells, patients undergo apheresis, which is a procedure in which we collect the subset of immune cells from the blood, the T cells from the blood.

Apheresis is a well-tolerated procedure, a vein to vein collection of collecting the T cells from the blood. T cells are in the lymph nodes, are in tissues, but they also are present in the blood. And we can use this technique to capture adequate number of T cells. They get sent off to the laboratory, genetically modified with a viral vector that infects only once and doesn't continue to replicate. And that permanently genetically modifies the T cells in the laboratory. When the cells finish, when we screen the cells, make sure that they're good to go, that there's no infection, contamination of the cells, and that they pass quality control. Patients then begin low-dose chemotherapy. So, they receive fludarabine and cyclophosphamide. This is called lymphodepleting chemotherapy. The chemotherapy is really I would consider it low-dose therapy. Now, this is for patients who've not had prior therapy. So, it's still chemotherapy and it can, in some settings, maybe even cause hair loss, temporary hair loss. It can cause nausea, can cause fatigue. But it's really given to prepare the patient to accept these genetically modified T cells after infusion of the chemotherapy. CAR T-cells are infused two days after the last dose of the cyclophosphamide. And it's a pretty small volume of cells that are infused because these are cells that have been modified in the laboratory and concentrated and purified. And the cells are infused intravenously. And it takes about two weeks for the cells to optimally proliferate and expand in the patient. And during this time, the T cells attack and destroy all of the patients B cells. So, it's really a very profound B-cell depletion. Similar to using rituximab, an anti-B-cell antibody, but even deeper tissue penetration, deeper tissue destruction of all of the B cells in the patient. The B cells are profoundly depleted for approximately three to four months. The hypothesis or the thing that we're testing is whether or not this profound B cell depletion is sufficient to achieve a true immune reset. Somehow by lack of B cell stimulation, the T cells that are contributing to the autoimmune disease basically die off because there's no co-stimulation or no signal to continue the ongoing attack against, in this case, muscle. This deep B cell depletion allows an effective reset of the immune system. After about four months, new naïve B cells emerge in the peripheral blood, and then the T-cell counts begin to also recover.

There are some potential complications from this therapy, like cytokine release syndrome, neurologic toxicity, something called ICANS, which can cause seizures or possibly even coma. And so, there are some risks in doing this. There's risks of infection, complications, and the immune cells don't recover immediately. It takes some months. During this time, we give prophylactic antibiotics, antiviral medications, sometimes antifungal, and other antibiotics to prevent infection complications during this time. Eventually, we see an immune recovery and an immune reset that occurs. And we're hoping to apply this promising therapy to patients with myositis.

I see this as a real paradigm shift because it's using cellular therapy to treat the disease. And the goal is to see if patients can be managed a long time without any ongoing immunosuppression. Dr. Seth, can you maybe talk about what that might mean for patients not being on long-term immunosuppression and what the promise of that might be?

Arjun Seth, MD : Yeah. I think it's great that this is being studied in the clinical trials setting right now to compare and look at the risks and benefits of doing something like this. And the early results, as you said, are promising. I think the potential benefit, yes, is being able to come off of some therapies or reduce the number of therapies that patients need, and then hopefully be quiet in terms of their disease. So, there's no ongoing progression of their muscle disease with active myositis and no other complications involving skin, lung, other organ systems as well. So, I think it can play a role, but really in more refractory cases.

I think because we have longer term data with IVIg, rituximab, as well as other immunosuppressants, we are better right now able to counsel patients on what to expect. Whereas with CAR T, this is still being studied. So, I think we just have to also be mindful as we're talking about it. Yes, it's very promising, but there are risks with it.

George Georges, MD (Moderator): True. And it is probably something more for patients who have failed to respond adequately to the therapies that we've discussed earlier today. It's really not the first-line of treatment, and rather something despite receiving several lines of therapy, at that time, consider this more experimental therapy.

This treatment, the CAR T therapy, has really been used for patients with lymphoma and has successfully brought patients into long-term durable remissions with their lymphoma. We don't yet know if CAR T therapy directed against B cells will achieve durable long-term remissions in patients with myositis. There are risks, including risk of death, including risk of serious infection complications with CAR T therapy. And yet, it offers a real shift in paradigm and shift in way of thinking about how to treat the disease. And you're right, it needs to be first studied in patients who have not responded adequately to the frontline therapies that we've discussed earlier. Do you think that CAR T therapy could eventually replace traditional treatments? Or is it still too early to tell?

Arjun Seth, MD : I think it might be. What do you think, Dr. Hsieh?

Christine Hsieh, MD: I mean, I think that there are a subset of patients who really could benefit from this type of novel therapy, but there's a fair amount of people who have mild disease, who are responding quite well to what we have available right now. And these are not the patients that I would refer for this. I do think that the risk, as you mentioned, the significant risks that happen with CAR T therapy far outweigh any potential benefits. But, you know, we all have patients that we can think of that, you know, we've sort of tried everything we can think of and we're still struggling to control their disease. And I think in those patients, it really is a benefit to be able to offer these opportunities to them. So, I don't think this will be for everybody. But I think the fact that we have this available is really an amazing kind of step for our patients who are really suffering sometimes.

George Georges, MD (Moderator): And in addition, I mean, there are other new technologies coming along, for example, like T-cell engager, bispecific antibodies that may also play a role. It's different than CAR T therapy. And there will be other new therapies in the future as well. But for consideration at this time, for patients who are refractory to several lines of therapy, this is certainly something to consider.

Arjun Seth, MD : Absolutely.

Christine Hsieh, MD: And it'll be very exciting if it does offer an immune reset for them and they can stay off medications for a prolonged period of time. I mean, it may not be forever. But, you know, five or 10 years off medications could be a significant quality of life improver for patients.

George Georges, MD (Moderator): It could be really substantial.

Arjun Seth, MD : It really would be.

Christine Hsieh, MD: Yeah.

Arjun Seth, MD : Yeah. I think there's more to learn, right? That's it at this stage. Absolutely.

George Georges, MD (Moderator): And we're really at the front lines of trying to offer this to patients here at Northwestern.

Christine Hsieh, MD: Yeah. The exciting thing is that I think there is real interest in this rare disease, which I think has not necessarily been at the forefront before. And I do think that there is real interest in finding targets for this condition, as well as doing well-designed randomized controlled trials and finding appropriate outcome measures for this, because I think we've struggled in our autoimmune conditions to really make well-designed trials that actually can show an outcome that benefits patients. And I think we learn in all our conditions. I mean, we were doing this with lupus where we didn't know what the best outcome measure is. And I think finally we're coming up with appropriate outcome measures for the inflammatory myopathies. And there's a real, like, interest in these trials. And so, there's many other things coming down the pipeline.

George Georges, MD (Moderator): Well, given the time that's elapsed, I think we've covered a really interesting, exciting topic. And I really want to thank you so much for joining me today and talking about myositis, the research that's been happening here at Northwestern and the CAR T program. So, it's been a real pleasure. Thank you so much.

Christine Hsieh, MD: Thanks.

Arjun Seth, MD : Thank you so much.

Christine Hsieh, MD: It's been fun.

Arjun Seth, MD : Yeah. Thanks so much.

Melanie Cole, MS (Host): Thank you all so much for such a lively discussion. Thank you again for joining us. And to refer your patient or for more information, head over to our website at breakthroughsforphysicians.nm.org/neurosciences to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole.