Ep. 219: Translational Neuroimmunology: Targeted Cellular Therapy for NMDAR Encephalitis

00:00:00: Welcome to EANcast, your weekly source for education research and updates from the European Academy of Neurology.

00:00:15: Hello everyone!

00:00:16: And welcome to the EAN podcast Weekly Neurology.

00:00:21: I'm Howard Pruis.

00:00:22: I am a clinical neurologist in Berlin leading the Department of Experimental Neurology at the Autoimmunity and Neurodegeneration section here at Charité University Hospital and I'm a neuroscientist at the German Center for Neurodegenerative Diseases.

00:00:38: And, i am very glad to have a specialist on my side which is Juna de Vries.

00:00:44: she's neurologist from the Netherlands at the Erasmus Medical Centre in Rotterdam Which as many of you may know the expertise centre for altimune encephalitis In The Netherlands!

00:00:56: And your focus is on care for Altimune Encephalytis patients.

00:01:02: care give us, you're training presidents and have a special interest in neuraminology and clinical research.

00:01:08: And I'm looking forward to discussion on today's topic which is Translation and Neurominology Targeted Cellular Therapy for NMDE Receptor & Surflites.

00:01:18: So welcome very much!

00:01:20: And i am looking forward our discussion maybe open with the question that what is NMD Ereceptor and Surflite?

00:01:29: What did we learn over almost twenty years now.

00:01:33: Harold, thanks for the kind introduction and it's really a joy to be on this year-end cast – really first time experience!

00:01:42: And yet you discuss what is at YNMDA receptor encephalitis?

00:01:47: It's really devastating disease affecting young especially women but also young men in the prime of their lives And you mentioned that it's almost twenty years ago, when it was discovered.

00:02:00: Professor Josef Tommel described twelve patients with devastating symptoms and showed they were caused by anti-NMDA receptor antibodies.

00:02:11: These patients often experience some kind of flu like symptoms so it can also mimic viral encephalitis with headache fever nausea And thereafter, the neurological and also philharmonic psychiatric symptoms develop.

00:02:27: So they often as you know have paranoia or delusions... ...and experienced seizures which can be really hard to treat.. ..and when disease progresses it's possible that they could have philhalmonic movement disorders... ...hypokinetic movement disorder but also fell in a coma have severe autonomic dysfunction.

00:02:51: So almost half or more has to be admitted on the ICU, so it's really a devastating disease.

00:03:00: I started my training in two thousand and six And then to illustrate what breakthrough actually is in neurology The discovery of this disease entities.

00:03:11: after the discovery of the NMDA receptor encephalitis A lot of more antibodies has been discovered.

00:03:19: So a lot of formerly unknown diseases were diagnosed nowadays, but when I was arrested there was a lady some twenty years ago with refractor status epilepticus and we couldn't save her.

00:03:34: she was four months in the ICU And then decided to stop treatment.

00:03:40: What's quite remarkable colleague of mine because he performed brain autopsy.

00:03:45: At that time, it wasn't kind of autoimmune encephalitis.

00:03:50: But twenty years later now we found in her brain the NMDA receptor antibodies.

00:03:57: So our colleagues from Barcelona just published a study That also really severe patients who are in coma for more than nine months can recover and regain independence.

00:04:11: Yeah, it's really a breaking point in the field and important to correctly diagnose these persons.

00:04:19: And yeah how can you make a diagnosis?

00:04:23: So first you have to be aware that this disease exists... ...and then you recognize these patients.. ..and they're really tricky because the MRI is often normal at first stages especially on the first time.

00:04:37: but up to yes seventy percent has a normal MRI And sometimes also, they don't show signs of inflammation in the CSF.

00:04:47: So you definitely have to order the antibody cell-based essay test and insert a amount of the patients about thirty percent who can fight it in blood so that you will still be able to get the lumbar puncture.

00:05:10: Trigas in your patient?

00:05:12: I mean, that's a remarkable story.

00:05:15: Yeah In this special lady we did not find the trigger but it is known half of young female patients have an ovary teratoma and then the elder patients because one out five patients are over forty-five.

00:05:32: But these patients can be found more carcinomas And they also recover slightly less well than the younger patients, especially with regaining recovery recoverance of cognitive functions.

00:05:49: But yeah but not in all patients we find a trigger.

00:05:54: also and no trigger is the herpes simplex encephalitis.

00:05:59: so when patients suffer from this viral form of encatholitis they start recovering after the antiviral treatments.

00:06:08: you see an in the part one out of four, about you see a second deterioration.

00:06:15: And then you say that it's not due to relapse of the virus or active becoming again active but its actually due to the autoimmune reaction.

00:06:28: most of time they find anti-NMDA receptor antibodies in these patients.

00:06:35: But yeah still not clear in a lot of patients why they become ill.

00:06:41: and it can you maybe her because your more into the really in depth disease mechanism comment on how?

00:06:51: yeah what are the immuno.

00:06:53: What is the immunopatrial?

00:06:54: visual or logically again, yeah NMDA.

00:06:58: any comment on that?

00:07:00: Yes so I mean we learned a lot over the last few years as you pointed out.

00:07:05: but still many questions are open.

00:07:08: So, I mean to me these teratoma cases in terms of simplest lexivirus and sublattice cases very informative how the antibody response is triggered.

00:07:20: but i think interesting question is this happening in the breath free most of time or depending on the central nervous system?

00:07:29: And similar to other autoimmune diseases the trigger happens preferably with maybe herpes as a flight is being partially an

00:07:40: exception,

00:07:41: even though that triggering of brain antigens probably also happened in peripheral lymph nodes.

00:07:47: But then interesting thing is are these B cells and plasma cells migrate into the brain?

00:07:53: And they were found at autopsy and biopsy studies to be deep in the parenchyma or along the meninges sometimes structures like we know from MS, right?

00:08:04: So that they form these tertiary lymphoic follicles.

00:08:08: And I think that's interesting also and i'm curious what you say about this when we come to treatment.

00:08:14: This may also make treatment more difficult if there is a brain response.

00:08:18: but the B-cells and plasma cells have to get in their first place.

00:08:26: Do you know what types of B-Cells are important for the disease mechanism of anti-NMDA here or septangular

00:08:34: colitis?

00:08:34: It seems that NMDA receptor encephalitis, especially in this case from other encefalitides we know most of the antibodies are highly hyper mutated.

00:08:44: Obviously there was intense interaction with the antigen in priming the moon response and NMDE receptor Encephalytes found some of these antibodies which you can see is even unmuted.

00:08:57: so it means this is germline sequences.

00:09:01: potentially most of the people like you and me have some NMDE receptor antibody producing these cells in their blood.

00:09:09: The question is then why do only very few patients develop NMDA receptor antibodies, encephalitis?

00:09:16: if they're antibodies are let's say in our genes anyway so that we all have them?

00:09:21: So definitely an interesting question which will be altogether need to solve for next few years.

00:09:28: And what were your thoughts?

00:09:30: maybe factors that make certain people more prone to develop.

00:09:36: Yeah,

00:09:37: I personally think there's a host factor so that with whether it is cytokine profiles or genetic background which i think its even more clear and other types of autoimmune diseases this may also play role.

00:09:51: thats individual Exposition exposures is one thing but that these host factors are another thing which is important to develop and the intercept answer flight.

00:10:04: And then maybe interacting with environmental factors like a secondary hit with fires or something else.

00:10:11: right all those things you can see even microbiome I think it's an interesting question of research in future, and potentially also responds to treatment may be very variable.

00:10:22: so maybe you can can explain a little bit what the current treatments are, so what's clinical practice?

00:10:30: How to approach your patients therapeutically.

00:10:34: What is important also for the listeners and clinicians out there on-the-floor that you already make diagnosis without positive tests.

00:10:45: So the gross criteria are important.

00:10:51: then they have to have a subacute onset and four key clinical symptoms, but also abnormalities in the CSF or on EEG.

00:11:02: So then you can already awaiting the antibody test start with first line immunotherapy.

00:11:09: what we started them in clinic is high dose IVS steroids in combination with IVRT And when your have the antibody tests back Or actually we wait with the IVIG when you have antibody test back.

00:11:25: So it's five days in a row, high doses In severe cases or other countries they don't have the availability of immunoglobulins.

00:11:36: so for example in Belgium day at in severe case stay at lesmophoresis.

00:11:42: We refilter out the etiological antibodies and if The patient doesn't respond within one or two weeks and they are severely affected.

00:11:53: Then we add a second line treatment, and it is a Rituximab.

00:11:57: so NTCD-II B cell therapy.

00:12:00: Or when they were really severely infected We also had cyclophosphamide.

00:12:06: But yeah And well I have the proportion of patients who were mildly affected.

00:12:11: then this start to improve already And then we repeat the cycle of first-line treatment after four and eight weeks.

00:12:19: But when it's not the case, we off course escalate.

00:12:24: So on one hand you have the immunosuppressive medication but in case there is a tumor or teratoma or cancer also as soon possible to start anti-tumor treatments or remove the tumour chemotherapy.

00:12:44: So that is how it's organized in our clinic.

00:12:48: and besides the disease specific treatments, we also treat a movement disorder.

00:12:56: so diseases are the psychiatric symptoms of course.

00:12:59: support to

00:13:03: patients yeah That's very interesting.

00:13:04: Also you mentioned plasma exchange which at least Germany quite common this condition.

00:13:10: but from a global perspective, it's probably slightly different.

00:13:16: As you mentioned IVIG is not always available.

00:13:20: or would you recommend in these cases to stick to steroids?

00:13:27: I'm personally not in favor of that but i know that given the lot and then... Yeah!

00:13:32: It depends on if a patient really is very effective.

00:13:36: they want have quick effect Plastrophoresis.

00:13:42: In milder cases, less often affected you can stick with the steroid.

00:13:51: But in German, do you give fewer steroids?

00:13:55: Yeah and NMD areas have to unsupply this.

00:13:57: it's often given at the beginning but we quickly move on then as suggested more specific treatments.

00:14:06: any patient for example end what we call targeted cellular therapies want to talk about today.

00:14:13: Yeah, yeah we don't give a taper of steroids and if they recover after a couple weeks you don't get the third cycle.

00:14:25: so also if you start the retiximab what we gave in a lot of patients... We don't gives that third cycle of steroids.

00:14:32: So it's also has especially psychiatric side effects which are not handy for having an NMDA.

00:14:43: Nowadays, we don't use the really disease-specific target therapies a lot.

00:14:48: Can you tell us what is meant by targeted therapy in this context?

00:14:54: It's a topic of the EN cast and it tells more about that.

00:15:05: neuro immunology in general treatments became more and more specific.

00:15:09: And as you already mentioned, I mean there was cyclophosphamide at some point.

00:15:13: now this retuximab with B cell depletion.

00:15:17: It seems that we are even more specific can also deeper neutralize these B cells and cellular therapies Sometimes I used as a term for depleting one subset of immune cells.

00:15:32: For example, depleting B-cells, retruxumab or plasma cells with dirotumomab and other treatments.

00:15:40: but i think what's really now also coming into the encephalitis field is heart T-cell so which we all have seen these exciting studies in hematology where patients with lymphoma B-cell lymphoma were treated so well, that they can now even talk about cure.

00:16:01: And CAR t-cells have been used in many neurological diseases over the last few years ranging from MS to myocenia gravis to stiff person syndrome with some remarkable successes also cases of course which it didn't work too well.

00:16:20: but this is something which has not being explored except from a few cases that are on their way, but I think that's an option.

00:16:31: also for NMDE receptor encephalitis because as you mentioned it is severe disease.

00:16:36: People have intensive care unit for lung periods of times and in your case with this patient there still a few patients nowadays who die from the disease usually on autonomic dysfunction or ICU complications.

00:16:49: so we need more Deeper depletion of the immune cells.

00:16:55: The good thing is what we know from Translational neuraminology is that it's really at the antibody in NME receptor and survivalized, so that causes a disease.

00:17:04: So the good thing if you get rid off their antibodies completely there are high chances of curing patients or getting them better even after longer hospital stays.

00:17:14: That why I think this is definitely a route to go.

00:17:18: whether CAR T-cells with all advantages and disadvantages will be a good balance.

00:17:24: We would see.

00:17:25: but in severe cases where we need to reach very deep B cell depletion, remove the B cells more or less entirely so that no novel enemy receptor antibodies can form I think thats something we should try.

00:17:41: whether this is part of an international study get more experience in our different centers with individual cases.

00:17:52: i think that's something we should discuss.

00:17:55: but the good thing is that.

00:17:57: In nmd receptor and syphilitis, you can learn so much from basic science approaches by cloning these antibodies by for example infusing them into a mouse brain.

00:18:08: really understand what it is the antibody that causes disease.

00:18:13: guide treatment may allow us also to take this risks for our patients to treat them with very deep immunosuppression, and achieve better recovery.

00:18:28: What do you think is the lack of effect on current treatments if compared to CAR-T cell therapy?

00:18:38: Why will that be more effective?

00:18:42: For example, with Rituximab we know that when you take lymph nodes from these patients to a biopsy You see the B-cells are still there.

00:18:51: many of this B cells.

00:18:52: After CAR T cell treatment The B-Cells and Lymph nodes are completely gone.

00:18:57: So I assume as you know one cannot take brain biopsies just for checking the treatment response.

00:19:02: But i'm quite confident That he would also see b-cell after RITUXIMAB treatment in the brain maybe in these follicles or the meninges and so on.

00:19:12: And it's highly likely from what we know from CAR-T cell treatments, other indications that these B cells are also wiped out.

00:19:21: this may give brain a chance for recovery.

00:19:26: Yeah!

00:19:27: They stay more rapidly recovered because they stay for months in the ICU.

00:19:34: And there's also, especially those long-living plasma cells which still are producing the antibody issue.

00:19:41: It is more difficult to attack them with the hybrotuxima treatment.

00:19:46: Absolutely!

00:19:46: I mean this would be of course a challenge for CD-IX B-cells but they're also Plasma cell targeting CAR-T cell approaches and in some cases it may still be enough.

00:19:58: The plasmas and niches also require b-cells, they develop from the B cell.

00:20:08: so if you cut them out early this may be sufficient in many of these situations.

00:20:12: But we will have to learn that!

00:20:15: Yeah but it's a good hope for future.

00:20:18: there is lot happening on the otomune field or broader otomume fields.

00:20:23: hopefully our patients can profit too.

00:20:28: And the good thing is, I mean these trials will come and i'm quite confident that they are.

00:20:34: They would be affected by.

00:20:35: but The question here.

00:20:36: so i'm glad That you're yes as this Is your your core expertise?

00:20:39: I mean what What has happened in the last few years towards better scores?

00:20:45: do You think we have now with what you developed it's out there the perfect tools Outnow to judge whether patients respond or not?

00:20:54: yeah because In the former trials and cohorts, we used to measure disease activity with the modified ranking skill which actually is a skill for stroke.

00:21:04: It's quite rough skills that doesn't really reflect long term sequels because patients can recover well in the sense of they are independent living their life but still have complaints especially cognition, the mood that you suffer from mood disorders sleeping problems.

00:21:30: So to cover that we need new outcome measures and also we have to empower a new clinical trials so you'd need less patients.

00:21:41: it's an extremely rare disorder disease of course but we have be really careful with our data in patient and try to empower them.

00:21:53: developed a patient-related outcome measure that the patients on a linear scale are covering several domains.

00:22:01: So cognitive function, mood but also fatigue and social functioning And it's actually published last week.

00:22:12: That is really important to have more sensitive discrimination value in outcomes better proof that the treatment is better than standard care.

00:22:27: So I think, and a difficult thing in acute phase they cannot fill out the form of course but we also have the case score.

00:22:39: it's clinical assessment skill and catholitis can be used by the clinician so thats already implemented doesn't really catch the long-term recovery, so it's a good sensitive method to measure disease activity in acute phase but on the long term its more difficult.

00:23:06: Congratulations from this paper and score.

00:23:08: I think that would be very useful.

00:23:11: One of our PhD students put a whole lot of work into this as commersure.

00:23:19: Do you think there's still room for the modified drinking scale score or such should not be used in this patient group anymore?

00:23:27: I think, for rough changes it can't be use but doesn't reflect the symptoms patients suffer from on long-term because everybody can walk and talk after one to three years.

00:23:43: But they have a lot of social life problems can also have forward findings problems, but it's more subtle.

00:23:53: So you'll also have to catch that with other outcome measures and then do a neuropsychological examination.

00:24:04: But this test is about... It costs ten-to fifteen minutes for the item scale And those are measures on linear base.

00:24:18: Yeah, measure change over time.

00:24:20: So it's really a useful extra tool.

00:24:25: I shouldn't rule out the address fully but its i think It can add yes read edge and need for other outcome measures as well.

00:24:40: yeah And we're working on is the prognostic modeling.

00:24:48: so you can maybe also compare current cohorts with historical cohorts.

00:24:56: You may be know the NEO score, which was published by Ballou in two thousand nineteen and that's actually an outcome score in NMDA receptor encephalitis where you can predict over one year later what is a result of treatment code to B?

00:25:14: And it quite good score.

00:25:16: only thing you have.

00:25:18: You can only use it for four weeks after the sort of treatment.

00:25:24: and what we really need in daily practice is when you make a diagnosis that, do know how the patient's going to respond?

00:25:35: And then also develop precision medicine so they can really make an individual treatment plan based on their prognosis or outcome over a year or even three years.

00:25:50: So that's another study we performed also led by Brenner, but it was an international cooperation with the German cohort and the Spanish, French and Japanese cohorts, several hundred patients.

00:26:05: so there are lots in NMDNR research.

00:26:11: You have subscales, so you can predict the response to first-line treatment.

00:26:14: So should you escalate or not in your first weeks?

00:26:18: And you could predict a long term outcome within year and also if they go back to school or resume their profession because that can take even longer than then for us here.

00:26:32: I think this can help make stratification in clinical trials.

00:26:38: Yeah, you increase your power by using these models.

00:26:44: So how do you think we can implement the CAR-T cell therapy and clinical trials?

00:26:50: How should we study that in the patient with oceamunicaphylitis?

00:26:57: What are thoughts on that?

00:26:59: I think it's really great to develop this course which will help us assess our patients longitudinally In particular, if we use more and more let's say aggressive or novel treatments.

00:27:13: the CAR T-SELTS is one.

00:27:14: I would also like to briefly mention the so called AA CAR T cells which i think could potentially be another next steps in a more intense treatment of these patients.

00:27:28: The principle behind AA CAR t-sels are that you take the patient's own T cells but then different to car t-cells, normal CAR T cells where you use an antibody fragment that binds a tumor cell for example.

00:27:44: We used a construct that binds NMDA receptor antibodies by basically placing piece of the NMD air receptor on top of patient's own T cells and we give these T cells back.

00:27:58: now is that patients B cells which produce NMDE receptor antibodies which have the NMDA receptor antibody in the membrane as a so-called B cell receptor.

00:28:10: They can bind against patients' own T cells and are depleted, they're basically killed by their own immune system.

00:28:17: This works surprisingly well with preclinical studies.

00:28:21: we did So in mice.

00:28:24: they can eradicate very specifically the Nmda receptor antibody response And we are now very curious to see whether this could also work in humans.

00:28:33: We have a great breakthrough,

00:28:38: if that works.

00:28:39: because you haven't read the specific tool

00:28:45: I hope so.

00:28:46: I mean theoretically like a surgeon with a knife cut out just one piece of immune system.

00:28:53: And if it works for NMDRs at the end cephalitis, that may also work for other types of encephalitis or even further autoimmune diseases.

00:29:00: My senior crevice,

00:29:02: e.g.,

00:29:02: all E-tion five disease.

00:29:04: so thats something we should of course explore and I'm really glad about this course.

00:29:10: The clinical metrics will help us to assess these patients in bringing these two fields together right?

00:29:16: So that you and i... have different focuses in this area, but it shows that we need the global network of colleagues working out to moon encephalitis.

00:29:26: To bring all these ideas together.

00:29:31: and do you also expect them because they are extreme side effects?

00:29:36: Especially when you're cute just after treatment will be less pronounced if your heart is more selective Treatment I can imagine.

00:29:48: Seems to be the case.

00:29:49: so we already learned from CAR T cells CD-NINDI CAR T cell in our immune diseases that for example the cytokine release and syndrome is much, much more as it's mainly determined at tumor patients by amount of tumors.

00:30:03: So if millions or millions of tumor cells are killed simultaneously get a lot of cytokines released but this population you have less auto reactive B cells with a double A card, he says you potentially even have just the handful of sets.

00:30:17: And then this hope comes along was much less side effects?

00:30:22: Yeah and it's wonderful if that is feasible in future.

00:30:26: yeah.

00:30:28: So I'm afraid we're coming to an end slowly.

00:30:31: so maybe from your perspective you now summarize what do think are current challenges and also future perspectives.

00:30:41: Yeah, I think what we learned in the last twenty years that NMDA is an important diagnosis for each neurologist.

00:30:49: That you recognize it and are aware of it And that its treatable disease because eight percent has a good response on treatments we give nowadays.

00:31:01: But there's still sequel and challenges.

00:31:04: We need to improve further treatment and the CAR T as explained really clear is some really promising treatment strategy for the future.

00:31:14: But as it's a rare disease, we have to reunite globally... ...to bring the patient together and perform clinical trials with good outcome measures which are really sensitive in measuring changes so that we can also prove efficacy of new treatment strategies be really helpful to use prognostic models.

00:31:41: So we hope that because nowadays about half of the patient is ending up in ICU, it can be for months but we can prevent and improve also long-term quality life of these patients.

00:31:58: Yeah so I think those are key things.

00:32:02: Off.

00:32:02: enemy reception can fly at such a moment and an empty air set right.

00:32:07: this is often example.

00:32:09: For all the other forms of switches algea one or Casper two are going to be we lot off.

00:32:15: you know, i love more of these disease.

00:32:18: of course that would really helpful for future to improve treatment strategies for these patients.

00:32:26: yeah I would fully agree here and can maybe add that As you said, what we learned from NMDA receptor and cephalitis.

00:32:34: We may be able to transform or translate into other encephalities.

00:32:39: And that's not only true for clinics.

00:32:41: so I think it is also the experimental work To understand how diseases are triggered How B cells develop?

00:32:49: Now with modern technologies have now You can really find out about entire group of diseases.

00:32:56: And I personally hope of course, and I'm slightly biased that these antibody selective treatments will develop further.

00:33:04: Actually even if cartesanates are not the last end-of-the line there may be other very specific treatments.

00:33:10: now people doing research on... In a few years we hopefully have very specific treatment available in kleptoprotein.

00:33:20: so i think thats really an exciting time.

00:33:25: Maybe as a final sentence, we shouldn't forget with all these successes that it still needs the neurologist to diagnose the disease early on.

00:33:35: And because if both parted out here... ...the early treatment is needed for better recovery and early treatments means early diagnosis right?

00:33:45: I think you will both agree on this.

00:33:47: Yeah, both are close in this patient's brain so sooner or later.

00:33:53: but yeah they're still still pay some patients who doesn't follow that rule and become very ill.

00:34:01: So we also have to try to figure out what can help those patients get these patients.

00:34:09: Thanks for enjoying this really nice discussion with you, thanks for being here!

00:34:14: Yeah, thank you Naya enjoyed it very much as well And would like to close the EAN cast now... ...and hope that you enjoyed it.

00:34:30: This has been EAN Cast Weekly Neurology.

00:34:34: Thank you for listening.

00:35:06: Thanks for listening!