Using the military analogy, it is like brainwashing your T-cells to become assassins, with only one mission to go around your body and kill all B-cells.
This treatment is pretty risky. The conditioning regimen is in the same ball park as AHSCT with leukpaenia, mucositis, hemorrhagic cystitis, infections, etc. Then there is the risk of infertility and secondary malignancies.
The actual CAR T-cells is associated with a cytokine release syndrome, which is likely to be less of a problem with treating pwMS because there is not a high tumour cell burden to lyse. There is an interesting CNS encephalopathy syndrome that happens with CAR T-cells that is likely to occur in pwMS. As the CAR T-cells traffic to the CNS and find their target and start killing them this will result in a form of encephalitis. Headache, confusion, seizures, reduced consciousness, focal neurological deficits can also occur. I suspect old MS lesions will be target and recrudescence of old symptoms will occur.
I suspect the more disabled you are the more the side effects will affect you. This is why this treatment is not for the faint hearted.
Dear dr Giovannoni, does this mean that person without B-cells in CNS - ie for example CIDP , has less a chance of encephalopathy syndrome considering CAR-T cells would travel where the B-cells are, or I have a wrong idea of it?
Also, is the dose of cyclophosphamide (about 1.6g for 60kg person) and 75mg/m2 fludarabine really comparable to side effects of AHSCT with 200mg/kg cyclophosphamide? I am confused because I read the studies and for example with cyclophosphamide only after cumulative dose of 9g there were a signs of damage to fertility in females. Thanks a lot, Petra
Hi Prof G, I’m interested in this therapy - how can I put myself forward for consideration? Does being on other treatments (potentially Myzent) exclude you from this?
Natasha, at the moment this therapy for MS is just in the planning phase and to the best of my knowledge in the US only. If a trial does get off the ground in the UK and/or Europe I will let you and the wider MS community know.
This needs significant de-risking it seems...but I am guessing medico-ethics boards would greenlight this for PPMS for lack of any other viable options?
To others who may not know Prof G as well as I do - I have been his patient for more than 10 years now and been reading his blog(s) and papers religiously: Now G had the guts to switch me to Natalizumab at a time when 2 other consultants in 2 different trusts would not (pre-PML risk profiling) and switched me to Alemtuzumab last year when a professor and national guidelines drafter refused to do so.
He is cautiously adventurous. If he says a treatment is risky, it is very risky. Please tread with a lot of caution.
Infected b cells in the CNS are probably harder to catch. How about combining T cell therapy with anti cd 20. Let them soldiers concentrate on the CNS?
Could Autologous be preferred over allogeneic t cells. The ATA188 embold study results kinda crushed our dreams a bit.
CAR T-cells will only be available via trials. These are only in the planning stage and are months/years away from starting. I will let you know via MS-Selfie when they are recruiting.
I was wondering how you think this will compare to AHSCT?
Am I correct in assuming that the autoreactive T-cells will remain in circulation and is that significant? Also I assume it is impossible to clear EBV as it will remain in the epithelial cells, so in that respect is it similar to AHSCT (in terms of B cell depletion), where the hope is that it doesn't reactivate/trigger MS? I guess it may be possible to use CAR T-cells to kill the plasma cells in the CNS which AHSCT won't achieve.
Not correct. The evidence that EBV cause latent infection of epithelial cells is not there. The evidence suggest it is still B-cells that infect epithelial cells that go through one lytic cycle of infection and are killed.
There are cases of people having AHSCT or HSCT becoming EBV negative and I am aware of one case with MS treated with alemtuzumab who became EBV negative. So I think anti-CD19 CAR T-cells may work by clearing out EBV infected B-cells, which is why this strategy needs to be tried in MS. Does this make sense?
Yes that makes sense, I hadn't realised it was possible to become EBV negative once infected. Many thanks for your responses, and it would be fantastic if it works!
Hi Josie, it's truly incredible to see how educated you are in terms of these new procedures. (And ofcourse dr Giovannoni also, but thats already very clear i think ;))
Re: "I was wondering how you think this will compare to AHSCT?"
Based on the SLE data it looks very promising. Dare I say superior to AHSCT? The reason for the latter is the CAR T-cells go and find B-cells to kill. With AHSCT you are simply using a sledgehammer that may not get to all the nooks and crannies where the pathogenic cells hide out,.
Re: "CAR T-cells to kill the plasma cells in the CNS which AHSCT won't achieve."
Yes and no. As CD19 is not expressed on plasma cells they should be resistant to this treatment. To killl plasma cells you would need to use anti-CD38 CAR T cells, but these would take out plasma cells throughout the body and increase the toxicity of the treatment.
Wen (Maxwell) Wang, M.D., Ph.D., Chief Executive Officer and Chief Medical Officer of IASO Bio, said, "As one of the first companies to conduct research on CAR-T to treat autoimmune diseases worldwide, our BCMA CAR T-cell therapy represents a significant milestone for Investigator Initiated Trial (IIT) data of relapsed and refractory NMOSD, an autoimmune disease with serious complications, blindness, and paralysis."
The study data initially showed that the Equecabtagene Autoleucel injection was safe in patients with relapsed/refractory NMOSD in the 0.5×106 CAR-T cells/kg and 1.0×106 CAR-T cells/kg dose groups. All patients experienced Grade 1-2 CRS (Cytokine Release Syndrome) and no Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) events. In terms of efficacy, all subjects observed improved Expanded Disability Status Scale (EDSS) scores after infusion. Fifty percent experienced improved visual acuity, 67% improved their walking ability, and 75% experienced improved bladder function. After a median follow-up of 5.5 months, 11 / 12 (92%) subjects did not observe any disease recurrence.
Ocrelizumab is not 100% effective and relapses do occur particularly during the first 6 months. We don't count these as a the drug failing and tend to rebaseline at 6 months.
Based on the oncology data CAR T-cells are likely to much more effective than anti-CD20 therapies.
This is seriously exciting science! I have very closely witnessed the amazingness of CAR-T therapy for cancer patients….to think that it might impact MS at some point in my lifetime with MS is humbling and super intriguing.
Yes. If EBV is the cause of MS and ongoing cycling between latent and lytic infection is driving MS disease activity then anti-CD19 CAR T cells may be a cure for MS. Now wouldn't that be amazing?
Any thoughts if this is an option for PPMS? AHSCT increasingly does not look like it is and OCR was never great.... Also, are you aware of anyone in Europe working on this? For a number of reasons (logistics among them), I am not keen on trials in the US (otherwise I would probably try to get into the ATA188 trial)...
No I am not aware of anybody using this treatment for MS in Europe. Even the US group had to put things on hold because of COVID-19.
Please be aware that this treatment is logistically very complicated and needs a lot of pieces of a jigsaw puzzle to be put in place to make things happen.
Can you explain why you think PPMS is not different to RRMS or maybe also SPMS, I'm really interested to know because living in Italy it seems there are different "schools of thought", For i.e. as you should know, here at diagnosis without active lesions, usually neurologists start Pwms treating'em with 1st line drugs like Tecfidera, Aubagio, interferon, GA, while in the USA from what I see prefere use big guns like Ocrevus, Kesimpta, Tysabri, etc,. Of course Italian neurologists must respect AIFA's rules and let patients worsen and accumulate disabilities.
Thanks for your quick answer Prof G, so CAR-T Cells treament should be similar to Ocrevus or Kesimpta? What do you think about the escalation model applied in Italy, is it obsolete in your opinion?
No anti-CD19 CAR T-cells would be better than ocrelizumab and ofatumumab as they will cross into the CNS and purge the CNS of pathogenic B-cells. Too little anti-CD20 antibody gets into the CNS to achieve this aim.
Very interesting, so the next step if it works could be remyelinating agents. Maybe I'm wrong but I think if EBV drives MS anche we clears the body of EBV and block inflammation maybe at least in the initial stage of the disease the body could recover stopping progression.
Is ata 188 a car T cell treatment? And yes study sd be done!! Sadly for me I now have perm. Disability. Even after cladribine I'm still progressing.though slower I think. I'm back on glatiramer which helps me w symptoms and hopefully stops my progression.
'Would you be interested in being treated with anti-CD19 CAR T cells as part of a clinical trial?'
I'm one of your MS patients, and I'd be willing to take part, if a trial is ever done I can access. I'm just starting to realise I won't be put forward for trials, and am trying to get into a couple myself.
I would be interested in being treated with car T cells if this is something even long term MSlers might have an improvement chance with…
I would love to learn more. Let's leave the money question on the side for now. What kind of risks are we talking about here?
This treatment is pretty risky. The conditioning regimen is in the same ball park as AHSCT with leukpaenia, mucositis, hemorrhagic cystitis, infections, etc. Then there is the risk of infertility and secondary malignancies.
The actual CAR T-cells is associated with a cytokine release syndrome, which is likely to be less of a problem with treating pwMS because there is not a high tumour cell burden to lyse. There is an interesting CNS encephalopathy syndrome that happens with CAR T-cells that is likely to occur in pwMS. As the CAR T-cells traffic to the CNS and find their target and start killing them this will result in a form of encephalitis. Headache, confusion, seizures, reduced consciousness, focal neurological deficits can also occur. I suspect old MS lesions will be target and recrudescence of old symptoms will occur.
I suspect the more disabled you are the more the side effects will affect you. This is why this treatment is not for the faint hearted.
You may find the SmPC helpful: https://www.medicines.org.uk/emc/product/9456/smpc#gref
Dear dr Giovannoni, does this mean that person without B-cells in CNS - ie for example CIDP , has less a chance of encephalopathy syndrome considering CAR-T cells would travel where the B-cells are, or I have a wrong idea of it?
Also, is the dose of cyclophosphamide (about 1.6g for 60kg person) and 75mg/m2 fludarabine really comparable to side effects of AHSCT with 200mg/kg cyclophosphamide? I am confused because I read the studies and for example with cyclophosphamide only after cumulative dose of 9g there were a signs of damage to fertility in females. Thanks a lot, Petra
p.s. there is a trial with NMO with BCMA CAR-T cells, published few months ago in China. I think promising there weren't neurotoxicity. However is there a possibly greater risk at devloping T-cells mediated autoimmune? https://www.prnewswire.com/news-releases/worlds-first-car-t-for-nmosd-treatment-iaso-biotherapeutics-equecabtagene-autoleucel-receives-ind-approval-by-nmpa-301609120.html?fbclid=IwAR3EOyuBHA4_2SQun1S001nlRXPviGICdnl3zCFH3BSJ5EfCM5XZN-FxfZ4
The ablation protocol is less severe than with AHSCT.
Hi Prof G, I’m interested in this therapy - how can I put myself forward for consideration? Does being on other treatments (potentially Myzent) exclude you from this?
Natasha, at the moment this therapy for MS is just in the planning phase and to the best of my knowledge in the US only. If a trial does get off the ground in the UK and/or Europe I will let you and the wider MS community know.
Thank you
It's risky. But all DMTs are risky. I will give you a detailed response when I have the time.
This needs significant de-risking it seems...but I am guessing medico-ethics boards would greenlight this for PPMS for lack of any other viable options?
To others who may not know Prof G as well as I do - I have been his patient for more than 10 years now and been reading his blog(s) and papers religiously: Now G had the guts to switch me to Natalizumab at a time when 2 other consultants in 2 different trusts would not (pre-PML risk profiling) and switched me to Alemtuzumab last year when a professor and national guidelines drafter refused to do so.
He is cautiously adventurous. If he says a treatment is risky, it is very risky. Please tread with a lot of caution.
I have had SLE for over 20 years and is moderately controlled by plaquenil. Do think this can also help with Ms?
Yes, yes, yes....
I am in the US, 54 years old, maybe PPMS, and interested to learn more about the trial.
Patfeller14@gmail.com
Thank you Dr. G!
Infected b cells in the CNS are probably harder to catch. How about combining T cell therapy with anti cd 20. Let them soldiers concentrate on the CNS?
Could Autologous be preferred over allogeneic t cells. The ATA188 embold study results kinda crushed our dreams a bit.
Hi, where can come in contact with you? I want to try the CAR-T-Cells method for MS, my email: Rensteeuwen@outlook.com
CAR T-cells will only be available via trials. These are only in the planning stage and are months/years away from starting. I will let you know via MS-Selfie when they are recruiting.
Hi I can you email me the info for the clinical trial at jkuhn8989@yahoo.com
Thanks!
Hi can you email me the info for the clinical trial to jkuhn8989@yahoo.com Thanks!
Many thanks for the information Prof G.
I was wondering how you think this will compare to AHSCT?
Am I correct in assuming that the autoreactive T-cells will remain in circulation and is that significant? Also I assume it is impossible to clear EBV as it will remain in the epithelial cells, so in that respect is it similar to AHSCT (in terms of B cell depletion), where the hope is that it doesn't reactivate/trigger MS? I guess it may be possible to use CAR T-cells to kill the plasma cells in the CNS which AHSCT won't achieve.
Re: "Also I assume it is impossible to clear EBV"
Not correct. The evidence that EBV cause latent infection of epithelial cells is not there. The evidence suggest it is still B-cells that infect epithelial cells that go through one lytic cycle of infection and are killed.
There are cases of people having AHSCT or HSCT becoming EBV negative and I am aware of one case with MS treated with alemtuzumab who became EBV negative. So I think anti-CD19 CAR T-cells may work by clearing out EBV infected B-cells, which is why this strategy needs to be tried in MS. Does this make sense?
Yes that makes sense, I hadn't realised it was possible to become EBV negative once infected. Many thanks for your responses, and it would be fantastic if it works!
Hi Josie, it's truly incredible to see how educated you are in terms of these new procedures. (And ofcourse dr Giovannoni also, but thats already very clear i think ;))
Re: "I was wondering how you think this will compare to AHSCT?"
Based on the SLE data it looks very promising. Dare I say superior to AHSCT? The reason for the latter is the CAR T-cells go and find B-cells to kill. With AHSCT you are simply using a sledgehammer that may not get to all the nooks and crannies where the pathogenic cells hide out,.
Re: "CAR T-cells to kill the plasma cells in the CNS which AHSCT won't achieve."
Yes and no. As CD19 is not expressed on plasma cells they should be resistant to this treatment. To killl plasma cells you would need to use anti-CD38 CAR T cells, but these would take out plasma cells throughout the body and increase the toxicity of the treatment.
Wen (Maxwell) Wang, M.D., Ph.D., Chief Executive Officer and Chief Medical Officer of IASO Bio, said, "As one of the first companies to conduct research on CAR-T to treat autoimmune diseases worldwide, our BCMA CAR T-cell therapy represents a significant milestone for Investigator Initiated Trial (IIT) data of relapsed and refractory NMOSD, an autoimmune disease with serious complications, blindness, and paralysis."
The study data initially showed that the Equecabtagene Autoleucel injection was safe in patients with relapsed/refractory NMOSD in the 0.5×106 CAR-T cells/kg and 1.0×106 CAR-T cells/kg dose groups. All patients experienced Grade 1-2 CRS (Cytokine Release Syndrome) and no Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) events. In terms of efficacy, all subjects observed improved Expanded Disability Status Scale (EDSS) scores after infusion. Fifty percent experienced improved visual acuity, 67% improved their walking ability, and 75% experienced improved bladder function. After a median follow-up of 5.5 months, 11 / 12 (92%) subjects did not observe any disease recurrence.
Hi,
I tried Ocrevus, and ended up having a flare-up of MS, as my B cells were depleted, would this occur if I tried CAR T-cell? Thank you! Nina
Ocrelizumab is not 100% effective and relapses do occur particularly during the first 6 months. We don't count these as a the drug failing and tend to rebaseline at 6 months.
Based on the oncology data CAR T-cells are likely to much more effective than anti-CD20 therapies.
This is seriously exciting science! I have very closely witnessed the amazingness of CAR-T therapy for cancer patients….to think that it might impact MS at some point in my lifetime with MS is humbling and super intriguing.
Yes. If EBV is the cause of MS and ongoing cycling between latent and lytic infection is driving MS disease activity then anti-CD19 CAR T cells may be a cure for MS. Now wouldn't that be amazing?
Any thoughts if this is an option for PPMS? AHSCT increasingly does not look like it is and OCR was never great.... Also, are you aware of anyone in Europe working on this? For a number of reasons (logistics among them), I am not keen on trials in the US (otherwise I would probably try to get into the ATA188 trial)...
No I am not aware of anybody using this treatment for MS in Europe. Even the US group had to put things on hold because of COVID-19.
Please be aware that this treatment is logistically very complicated and needs a lot of pieces of a jigsaw puzzle to be put in place to make things happen.
As you know i don't think PPMS is any different to relapsing MS therefore this treatment would work in both relapse-onset MS and PPMS.
Can you explain why you think PPMS is not different to RRMS or maybe also SPMS, I'm really interested to know because living in Italy it seems there are different "schools of thought", For i.e. as you should know, here at diagnosis without active lesions, usually neurologists start Pwms treating'em with 1st line drugs like Tecfidera, Aubagio, interferon, GA, while in the USA from what I see prefere use big guns like Ocrevus, Kesimpta, Tysabri, etc,. Of course Italian neurologists must respect AIFA's rules and let patients worsen and accumulate disabilities.
https://gavingiovannoni.substack.com/p/is-primary-progressive-ms-a-different#details
Do CAR T-cells fight and target EBV?
Anything that takes out B cells is ANTI-EBV. Memory B cells is where latent EBV hangs out.
Thanks for your quick answer Prof G, so CAR-T Cells treament should be similar to Ocrevus or Kesimpta? What do you think about the escalation model applied in Italy, is it obsolete in your opinion?
No anti-CD19 CAR T-cells would be better than ocrelizumab and ofatumumab as they will cross into the CNS and purge the CNS of pathogenic B-cells. Too little anti-CD20 antibody gets into the CNS to achieve this aim.
In your opinion it will put MS in remission for i.e. years, or should it be considered a cure or just a therapy?
If EBV drives MS and this treatment clears the body of EBV it may be a cure. This is why it needs to be investigated further.
Very interesting, so the next step if it works could be remyelinating agents. Maybe I'm wrong but I think if EBV drives MS anche we clears the body of EBV and block inflammation maybe at least in the initial stage of the disease the body could recover stopping progression.
Is ata 188 a car T cell treatment? And yes study sd be done!! Sadly for me I now have perm. Disability. Even after cladribine I'm still progressing.though slower I think. I'm back on glatiramer which helps me w symptoms and hopefully stops my progression.
No the Atara product is not engineered.
'Would you be interested in being treated with anti-CD19 CAR T cells as part of a clinical trial?'
I'm one of your MS patients, and I'd be willing to take part, if a trial is ever done I can access. I'm just starting to realise I won't be put forward for trials, and am trying to get into a couple myself.