Will Meador, MD (Host): Welcome to Better Edge, Northwestern Medicine Podcast for physicians. I'm Will Meador, your host. I'm an Associate Professor of Neurology at the University of Alabama at Birmingham. We're hosting a panel discussion today on the topic of paraneoplastic syndrome, as well as recent updates from the AAN or American Academy of Neurology Annual meeting.

Joining us today, we have two experts from Northwestern Medicine. Dr. Ditte Primdahl is an Assistant Professor of Neuro-Oncology and Neurological Surgery; and Dr. Shailee Shah, Clinical Assistant Professor of Neurology in the Division of Multiple Sclerosis and Neuroimmunology. Dr. Primdahl and Dr. Shah, welcome to the podcast. I'm excited to learn from you today.

Shailee Shah, MD: Thanks so much for having us.

Host: Dr. Shah, we'll start with you. Do you want to share some highlights from some of the exciting session you attended at the AAN?

Shailee Shah, MD: Yeah. So, when it came to autoimmune and paraneoplastic disorders, there were quite a lot of discussions and updates about the autoantibodies that we typically associate with cancers and frequently conversations about these patients who not only have paraneoplastic syndrome associated with autoantibodies, but have these in the context of receiving what are called immune checkpoint inhibitors, which work to essentially kind of unleash the immune system in order to target the cancer. And so, these are patients in whom you're balancing autoimmunity and these immune checkpoint inhibitors and trying to make sure that a patient's cancer is getting better while simultaneously making sure that their neurologic disease is getting better.

There has been some additional updates on some of these patients. In particular, the ones that have antibodies who tend to have much more severe disease in the context of immune checkpoint inhibitors and updates about additional immunosuppressive treatments that can be used at the same time as these immune checkpoint inhibitors in select group of patients, usually more targeted treatments that allow you to continue to treat both at once.

Host: It's really interesting. I guess you have to be careful with combined therapy and aggressive immunosuppression as well with that.

Shailee Shah, MD: Right, right, right.

Host: Dr. Primdahl, what about you? What did you take away from the AAN?

Ditte Primdahl, MD: A couple of things. I think kind of to move and build on what Dr. Shah just said, one thing that I found very fascinating and I think will be part of the future is going to be how we obviously treat paraneoplastic syndrome, which is a big part, but also balancing that with the treatment of cancer.

And in that regard, one of the sessions that I really enjoyed was when they presented a couple of cases where they have treated, and it was a little bit different. It was autoimmune diseases, they were refractory. So again, it's your immune system kind of being overactive and they were not able to control patients' symptoms with immunosuppressive therapy like steroids, IVIG, et cetera.

So, what they had done was treating them with CAR T-cells, so CD-19-directed CAR T, which for me as a neuro-oncologist, I felt was this very interesting and very interesting approach. Because to what Dr. Shah said, what we typically do, if we have a paraneoplastic syndrome in setting of a cancer, especially if the cancer patient is being treated with immune checkpoint inhibitors, which the goal of that is to boost the immune system. If we want the paraneoplastic syndrome controlled, we like to suppress the immune system. So, it's kind of like you're pushing the accelerator and the brakes at the same time. So, to that exact point, do we want to try to treat the paraneoplastic syndrome, compromising the care of the cancer, knowing that treating the underlying cancer is also part of treating the paraneoplastic syndrome. So, this is a challenging situation to be in.

But anyway, what they had presented was treating some patients not paraneoplastic, but autoimmune with CD-19 CAR T-cells, so therefore not using steroids. And these patients, granted it was peripheral neuropathic syndromes, but they didn't have for instance, ICANS, et cetera. So, I felt that was very interesting. And also, as neuro oncologist thinking, is there way we could then target, maybe design the cars so they could attack both the immune system for the paraneoplastic syndrome and also treat their cancer. Like, that would be a very elegant way of treating paraneoplastic syndromes and cancers at the same time. So, that was one of the things for me, the treating aspect of it, that was very intriguing.

Host: Yeah. And the CAR T therapies seem pretty limitless, right? When you really train these cells to go after targets that you want them to go after. So, that is really exciting.

Shailee Shah, MD: And, you know, we're exploring them in neurologic disease. And so, our hope is that this will be a very positive outcome with the different diseases they're using them in. And we can apply them to more and more. And as you said, try sort of more elegant approaches to this in the future for patients who have dual competing pathologies. I think it's a very exciting thing.

I think one thing that's going to be really important moving forward to all, for all this, is that oncologists and neurologists will have to be working quite closely together when it comes to treating these patients. And there will likely be a lot of complexity involved, especially at first as they can't figure out how to go about it.

Host: It's really exciting to go to these talks and see cutting-edge therapies or innovations. And then, you get back to the clinic, right? Or back to your office. So Dr. Shah, how are you going to integrate some of the things you took away from the AAN into your everyday practice.

Shailee Shah, MD: Into my everyday practice, I think, and really into anybody, any neurologist's, oncologist's everyday practice, I think the things that are worth sort of taking away, more broadly speaking are how to recognize these syndromes and how to actually diagnose them. These are patients who typically present with these subacute onset of neurologic symptoms. Usually, there are very specific phenotypes that are associated with these diseases, things like limbic encephalitis, myelitis, a rapidly progressive cerebellar syndrome. All of these particular phenotypes can also overlap, which can be included in the diagnosis, and these can frequently happen in patients who have a longstanding history of tobacco abuse or patients in whom there have been other b symptoms, weight loss, fevers, chills, other constitutional symptoms or suggestion of something else going on.

One of the exciting things that's been talked about recently is that diagnostic criteria for paraneoplastic syndromes, which were discussed in several of the topics, several of the lectures at the AAN. The main components of the new criteria that was created is looking at the syndromes in the context of what are called high risk autoantibodies and also categorizing certain phenotypes as higher risk and others as lower risk. This, in combination with the presence of a cancer or the identification of a cancer over a several two-year period of time can essentially be used to create a score that tells you about the likelihood of having a paraneoplastic syndrome.

Host: And is that building upon like the APE2 score that's been published in the past?

Shailee Shah, MD: Yes, exactly. It almost works in parallel with it in a lot of ways because when we're talking about the APE2 score and the right scores, we're talking about the autoimmune encephalopathy or encephalitis scores, or the likelihood of having an autoimmune seizure disorder, epilepsy, things more like LGI1, NMDA, that sort of thing. And then, this works almost complimentary to that because this work gives us more on those autoantibodies that have a little bit of a higher association with cancers. Things like ANA1 or anti-Hu or anti-Yo, PCA1, those sorts of things.

Host: And Dr. Primdahl, what about you? How are you going to incorporate changes in your practice based on what you learned?

Ditte Primdahl, MD: I think a big part of what I took away from the meeting as well was how do we predict, how can we predict this, especially in the setting of so many emerging therapies in the oncologic world, when they use not only CAR T, but also when they use BiTE therapies, other things that will kind of ramp up the immune system, is there a way that we can predict, foresee things that we can do from the get-go to prevent? Things like that. And so, Dr. Shah and myself are opening a formal paraneoplastic clinic. We're hoping to more longitudinally follow these patients, because that way we can collect some of that data to better understand not just like while they're inpatient in the acute setting, but also over time and maybe even before. So, getting that full vision and the scope of the disease course and understanding it better. They talked a lot about like predictive biomarkers, diagnostic biomarkers, et cetera, both in the serum, but also in the CSF. So, some that will be interesting going forward.

Host: That's exciting about the clinic. So cohorting, the patients will really help you learn how to manage these individuals and how they do over time. That's exciting. So, you gave a presentation at the AAN annual meeting on paraneoplastic syndromes together. And so, do you want to share some kind of key takeaways or notable highlights from that talk?

Shailee Shah, MD: So, one of the things that we haven't yet mentioned was essentially that there was kind of a lot of talk about the use of some of these biomarkers, including specifically a certain type of sort of genetic testing and also, specifically using these sort of omics that allow us to better understand or better identify certain autoantibodies, that the idea is that there's this sort of techniques that we can use to identify previously unknown human autoantibody antigens, and using sort of sequences available on the CSF or serum, and typically using a sort of phage display platform

Host: That's exciting. I know testing is a hot topic, as far as getting the right tests and the right patient and screening and finding the right antibodies. And hopefully, that procedure or process would help us deal with those false positives that we sometimes get on some of the larger panels as well.

Shailee Shah, MD: Yeah.

Ditte Primdahl, MD: Yeah.

Host: As far as other things, if for colleagues who weren't able to make the meeting, anything else that you'd like to share, Dr. Primdahl, with your colleagues who couldn't make the meeting that you took away?

Ditte Primdahl, MD: I think one of the advantages of going to this meeting is, in a field with a rare disease, that we all have to learn from each other. And I completely understand sometimes you can't go, but what I realized going is that the network is so good, but it's also available even when you're not there. For instance, there are various, like the dinners for autoimmune disorders, paraneoplastic, and being established and being part of that throughout the year, not just at AAN like they do webinars, et cetera. And for me, we're all busy clinicians, so we can't attend all the time. But the virtual options of every once in a while, there's a journal club or webinar, I learned more about different options just being there. And that's something, you know, you can look up different things that are available, not just at AAN but year-round, just to kind of try to keep up with this emerging field.

Host: That's great advice for sure, to stay connected, as always. Anything else you'd like to share from the meeting, Dr. Shah?

Shailee Shah, MD: You know, I think that, honestly, that really summarizes it, which is that trying to stay connected, trying to be involved, getting involved in different projects and in lectures, both sort nationally and internationally is really what will ultimately push the field forward. I think we're kind of excited to build this paraneoplastic clinic here. But I think, ultimately, it's also going to open doors for us to collaborate with others across the country too, and be able to kind of share data amongst all these different sites, which we're fairly excited about.

Ditte Primdahl, MD: Also local provider, like people in the community, it can be very hard even when you're in a big academic center to get the expertise just because it is rare. So, collaborating with people in the community that might not feel very comfortable managing these patients, that people can reach out to some of these bigger academic centers that plant the flag, so together we can obtain this knowledge and learn how to best treat these patients.

Host: It sounds like there's a bright future for paraneoplastic syndrome patients, so you're doing great work there at Northwestern Medicine.

Shailee Shah, MD: We try to think so.

Host: Thank you for joining us today for the podcast. To refer any patients, you can hit on over to the website at breakthroughforphysicians@nm.org/neuro, to get connected with one of our providers. That wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Will Meador, and thank you for joining us.