EBV targeting treatment yields clinical improvements in spms

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1eye
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Re: EBV targeting treatment yields clinical improvements in

Post by 1eye »

Just got this reply.

Guess we'll have to wait for multicentre trials, if they ever happen. Oh, well, I didn't need the gadolinium... BTW he has a patent on the therapy...
Dear Chris

Thank you for your interest in our work. We are planning to undertake a phase I clinical trial of EBV-specific adoptive immunotherapy in 5 patients with secondary progressive MS and 5 patients with primary progressive MS. Participants will be recruited directly through the MS Clinic at the Royal Brisbane and Women’s Hospital. Because there are already a large number of people in Brisbane wishing to participate in the proposed trial, at this stage we are unfortunately unable to consider requests for participation from people outside of Queensland. I wish you all the best.

Yours sincerely

Michael Pender
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Anonymoose
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Re: EBV targeting treatment yields clinical improvements in

Post by Anonymoose »

Hi 1eye,

I don't know how Canadian health care works but maybe you could try getting an oncologist at a cancer center to give you the treatment. Adoptive immunotherapy is already used for some ebv related cancers...

I was going to try myself but seem to be doing quite well after rituxan/valtrex so I'm currently just sitting around waiting for my ms to act up before pursuing further treatment. There is a nih study in the US treating with intrathecal and iv rituxan (what I did with different dose schedule) that you might be able to get in on. It's obviously not the same as AI but would hit the same target.

I think exploring anti-ebv treatment is a fairly promising route to take. There are multiple options for doing so. If you want to go there, just keep trying.


GL!
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1eye
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Re: EBV targeting treatment yields clinical improvements in

Post by 1eye »

Anonymoose wrote:Hi 1eye,

I don't know how Canadian health care works but maybe you could try getting an oncologist at a cancer center to give you the treatment. Adoptive immunotherapy is already used for some ebv related cancers...

I was going to try myself but seem to be doing quite well after rituxan/valtrex so I'm currently just sitting around waiting for my ms to act up before pursuing further treatment. There is a nih study in the US treating with intrathecal and iv rituxan (what I did with different dose schedule) that you might be able to get in on. It's obviously not the same as AI but would hit the same target.

I think exploring anti-ebv treatment is a fairly promising route to take. There are multiple options for doing so. If you want to go there, just keep trying.


GL!
From the Pender/Burroughs paper:
Prevention

Vaccination of healthy EBV-seronegative young adults with recombinant gp350 prevents the development of AIM induced by EBV infection, although it does not prevent asymptomatic infection.150 After vaccination, there was seroconversion to anti-gp350 antibodies persisting for >18 months and accounting for the protective effect, given that anti-gp350 antibody neutralizes EBV infectivity.151 Vaccination of rhesus monkeys with soluble rhesus lymphocryptovirus gp350 not only protects against infection but also reduces viral loads in animals that become infected with virus after challenge.152 As AIM increases the risk of MS,37 vaccination with gp350 might decrease the occurrence of MS by reducing the occurrence of AIM. By reducing the infectivity of EBV, it might prevent MS also in people who would not have developed AIM after EBV infection. Vaccination against EBV latent proteins also has the potential to prevent MS.
Treatment

There are 3 ways to treat MS by controlling EBV infection: (1) B-cell depletion with monoclonal antibodies, (2) antiviral drugs and (3) boosting immunity to EBV. B-cell depletion with rituximab reduces inflammatory brain lesions and clinical relapses in patients with relapsing–remitting MS141 but has the disadvantage of indiscriminately killing, not only EBV-infected B cells but also all uninfected B cells, thereby impairing protective humoral immunity against infectious agents, including EBV.

With regard to antiviral drugs, therapy with aciclovir, which inhibits herpesvirus DNA polymerase, 2.4 g daily for 2 years decreased the relapse rate by 34% in patients with relapsing–remitting MS (P=0.08).153 In a subsequent study, treatment with valaciclovir 3 g daily for 24 weeks reduced the number of new active MRI brain lesions in a subset of MS patients with high levels of MRI-evident disease activity.154 The limited efficacy of aciclovir and valaciclovir in MS might be due to the fact that these drugs act on EBV only when it is using its own DNA polymerase to replicate its DNA. This will apply only to lytically infected cells, but not to latently infected cells, which replicate EBV DNA by using EBNA1 to engage host-cell DNA polymerase. Thus, these antiviral drugs will inhibit EBV in only the minority of the EBV-infected B cells in the brain that are lytically infected but not in the majority that are latently infected.115 An alternative approach is to target the main latent proteins expressed by EBV-infected B cells in the brain in MS, namely LMP1, LMP2A and EBNA1.115, 127 This approach is exemplified by the use of small interfering RNA targeting the LMP1 gene to downregulate LMP1 expression and induce apoptosis in EBV-infected LCL,155 and by the use of small molecule inhibitors of EBNA1.156 Drugs inducing apoptosis of EBV-infected cells by inhibiting EBV-encoded anti-apoptotic proteins such as BHRF1157 might also be beneficial in the treatment of MS.

Improving immunity to EBV in people with MS could be achieved by vaccination with gp350 or EBV latent proteins, administration of humanized or human monoclonal antibody against gp350, or by the infusion of in vitro-expanded autologous EBV-specific CD8+ T cells. Treatment with autologous EBV-specific cytotoxic CD8+ T cells is beneficial in patients with EBV-induced post-transplantation lymphoproliferative disease158 and EBV-associated metastatic nasopharyngeal carcinoma.159 This approach should be feasible in MS because, despite the quantitative deficiency of EBV-specific CD8+ T cells, it is possible to generate EBV-specific CD8+ T-cell lines by in vitro stimulation with autologous LCL.75 Furthermore, EBV-infected B cells from MS patients are not resistant to killing by CD8+ T cells, because EBV-infected LCL from MS patients can be killed normally by HLA-matched EBV-specific CD8+ T-cell clones from healthy subjects, as well as by autologous EBV-specific CD8+ T-cell lines.75

AdE1-LMPpoly is a novel recombinant adenovirus vector encoding multiple CD8+ T-cell epitopes from three EBV latent proteins, namely EBNA1, LMP1 and LMP2A.159 Adoptive immunotherapy with autologous T cells expanded in vitro with AdE1-LMPpoly increases survival in patients with metastatic nasopharyngeal carcinoma, where the EBV-infected carcinoma cells express EBNA1, LMP1 and LMP2A.159 As EBV-infected B cells in the brain in MS express the same three EBV proteins,115, 127 adoptive immunotherapy with AdE1-LMPpoly might be an effective way to increase the number of CD8+ T cells available to eliminate EBV-infected B cells from the CNS in MS. Recently, this approach was used to treat a patient with secondary progressive MS.142 EBV-specific T cells from the patient’s blood were expanded by in vitro stimulation with AdE1-LMPpoly and interleukin-2. After expansion, 38.46% of CD8+ T cells, but only 0.22% of CD4+ T cells, reacted to the LMP peptides within AdE1-LMPpoly. The EBV-specific T cells were returned to the patient intravenously at fortnightly intervals. To reduce the risk of aggravating CNS inflammation, an initial dose of 5 × 106 T cells was administered, which is 25% of the median dose used for nasopharyngeal carcinoma,159 with gradual escalation of the dose over the following three infusions to 1 × 107, 1.5 × 107 and 2 × 107 cells. The treatment was successfully completed without significant adverse effects. Following the treatment, the patient experienced a reduction in fatigue and painful lower limb spasms, an improvement in cognition and hand function, and increased productivity at work. These improvements were sustained up to the time of the latest review, 21 weeks after the final T-cell infusion, when neurological examination demonstrated increased voluntary movement of the lower limbs. Following treatment, the frequency of circulating EBV-specific CD8+ T cells increased and there were decreases in intrathecal IgG production and disease activity on brain MRI.142 The beneficial effects of the therapy were attributed to the killing of EBV-infected B cells in the CNS by the adoptively transferred CD8+ T cells.

The adoptive transfer of EBV-specific CD8+ T cells in MS is not without risk. The transferred T cells could aggravate inflammation in the CNS and actually worsen MS, either through cross-reactivity between EBV and CNS antigens or through bystander damage. Clinical trials are needed to determine first the safety and then the efficacy of EBV-specific adoptive immunotherapy in a larger number of patients with progressive MS. In view of the potential risk of aggravating CNS inflammation, this therapy should probably not be tried yet in patients with relapsing–remitting MS, for which a number of disease-modifying therapies are already available.147 Another important question is how long any beneficial effect of EBV-specific adoptive immunotherapy in MS is likely to last. As the therapy does not correct the generalized CD8+ T-cell deficiency that might underlie the impaired CD8+ T-cell immunity to EBV in MS,77, 78 it is likely to be that EBV-specific CD8+ T-cell immunity might eventually wane again after the initial increase from immunotherapy. If such a decrease is accompanied by worsening of MS, consideration should be given to administering a further course of EBV-specific adoptive immunotherapy.
Conclusion

Given the rapidly accumulating evidence for a role of EBV in the pathogenesis of MS, there is ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection. Strategies to control EBV infection include vaccination against EBV, antiviral drugs and adoptive immunotherapy with EBV-specific cytotoxic CD8+ T cells.
Conflict of interest

SRB holds a patent on the EBV epitopes included in the AdE1-LMPpoly construct. MPP declares no conflicts of interest.
SRB is probably Dr. Scott Burroughs, and MPP would be Dr. Pender.

Health care in Canada is very insular and sensitive to turf trespassers. The attitude I have seen is that since "MS" is not considered as a fatal condition, there can be no off-label or experimental treatment for it. Basically the "MS" group of patiemts is seen as a gravy train for the drug/research medico-industrial complex. It is not meddled with, without all i's dotted, t's crossed, all three phases of trials, and approval by the FDA and Health Canada. If I could find such an oncologist or anybody willing to administer some kind of EVB targeted therapy, it would likely be in the US, and cost me a lot of money, even though I am supposedly insured. I could not only be playing guitar, I could be driving to the six-figure job I had, but the insurance company won't move without the medical mafia's approval.

I would be better off in the country of my birth.

Can I get my kids vaccinated?

There are those who are shot and killed in the hours before an armistice comes into force.
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Re: EBV targeting treatment yields clinical improvements in

Post by Leonard »

The article by Pender and Burrows mentions 3 ways to treat MS: B-cell depletion with monoclonal antibodies, antiviral drugs and boosting immunity to EBV.
I wish to deepen the first option bit further.

B-cell depletion by Rituximab is mentioned, rituxan is a monoclonal antibody but may have some disadvantages as Pender says.

Also this new development by GeNeuro is for a monoclonal antibody, an IgG4 antibody for treatment of MS. The article mentions EBV.
http://www.geneuro.com/files/documents/BWT12032014.pdf

Personally I am very interested in IgG3 as a possible way to treat MS.
IgG3 (Vivaglobulin) was successfully used to treat CFS and fybromyalgia and knock-down the EBV and other infectious agents.
IgG3 helps strengthen the immune system, helps the B-cells with the right armory.
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Re: EBV targeting treatment yields clinical improvements in

Post by David1949 »

I take this as good news. At least this was done on a human MS patient, not a mouse. This was done on a patient at EDSS 8, meaning bed-ridden. I f he gets out of bed and starts dancing we will have real cause for celebration. Let's hope that happens. Or maybe future studies will show a reduction in EDSS score for many patients. That would be fantastic.
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Re: EBV targeting treatment yields clinical improvements in

Post by Anonymoose »

About that decreased CSF IgG...

IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments
http://www.hindawi.com/journals/msi/2015/296184/

Pender's patient is mentioned (needs more investigation). So is rituxan (fails to deplete IgG, author questions whether repeated intrathecal administration might work).
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Re: EBV targeting treatment yields clinical improvements in

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I recently contacted Prof Pender to find out how is research is going. He is currently still gathering funds for a clinical trial.
Pender wrote:We are planning to undertake a phase I clinical trial of this therapy in 5 patients with secondary progressive MS and 5 patients with primary progressive MS. The symptomatic improvement of our first patient has now been sustained for over 18 months since the final T cell infusion.
I would of liked to know more if the improvements keep increasing, but he of course would be expected to keep professional reservation. It also makes me wonder why they are not trying this treatment on RRMS? although I am not complaining :wink:
Pender wrote:We have obtained the ethical approvals but have not yet obtained the full funding required. We hope that this will occur within the next few months.
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Re: EBV targeting treatment yields clinical improvements in

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CureOrBust wrote:I recently contacted Prof Pender to find out how is research is going. He is currently still gathering funds for a clinical trial.
Pender wrote:We are planning to undertake a phase I clinical trial of this therapy in 5 patients with secondary progressive MS and 5 patients with primary progressive MS. The symptomatic improvement of our first patient has now been sustained for over 18 months since the final T cell infusion.
I would of liked to know more if the improvements keep increasing, but he of course would be expected to keep professional reservation. It also makes me wonder why they are not trying this treatment on RRMS? although I am not complaining :wink:
Pender wrote:We have obtained the ethical approvals but have not yet obtained the full funding required. We hope that this will occur within the next few months.
I think Pender is a cautious (and very nice, brilliant, yadda yadda) guy. He seems reluctant to go the rituxan route (a relatively safe therapy that's been used for various conditions for years) because it depletes most B cells, lowering overall immunity, and doesn't affect the infected plasma cells or non-b infected cells. My guess is he is worried the infused T cells might attack healthy tissues in msers making their condition worse so he is only including patients with few other treatment options. I'm glad those with progressive ms are getting the chance. Also, he may be cautious but he doesn't drag his feet. If it works, Pender will move it along as quickly as red tape and funding will allow. :)

I wonder, once he's gathered more proof of benefit, how long it will take other docs to apply a treatment already in use for cancer to ms? That's where things get muddied for me.
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Re: EBV targeting treatment yields clinical improvements in

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http://www.ncbi.nlm.nih.gov/pubmed/25939660

Antivirus immune activity in multiple sclerosis correlates with MRI activity.
OBJECTIVE:
The objective of this study was to determine whether reactivation of Epstein-Barr (EBV) or activation of the anti-EBV immune response correlates with MS disease activity on MR imaging.

METHODS:
Subjects with early, active relapsing-remitting MS were studied for 16 weeks with blood and saliva samples collected every 2 weeks and brain MRI performed every 4 weeks. We isolated peripheral blood mononuclear cells from each blood sample and tested the immune response to EBV, autologous EBV-infected lymphoblastoid cell lines (LCL), human herpesvirus 6 (HHV6), varicella zoster virus (VZV), tetanus, and mitogens. We measured the proliferative response and the number of interferon-γ secreting cells with ELISPOT. We measured the amounts of EBV, HHV6, and VZV DNA in blood and saliva with quantitative PCR. On MRI, we measured number and volume of contrast enhancing and T2 lesions. We tested for correlation between the immunologic assays and the MRI results, assessing different time intervals between the MRI and immunologic assays.

RESULTS:
We studied 20 subjects. Ten had enhancing lesions on one or more MRI scans and one had new T2 lesions without enhancement. The most significant correlation was between proliferation to autologous LCL and the number of combined unique active lesions on MRI 4 weeks later. Both proliferation and number of cells secreting interferon-γ in response to LCL correlated with the number of enhancing lesions 8 weeks later.

CONCLUSIONS:
We find evidence for correlation of antiviral immune responses in the blood with subsequent disease activity on MRI scans
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Re: EBV targeting treatment yields clinical improvements in

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Thank you, study is highly relevant.
Last edited by Leonard on Fri May 08, 2015 1:50 am, edited 1 time in total.
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Leonard
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Re: EBV targeting treatment yields clinical improvements in

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1eye wrote:

Health care in Canada is very insular and sensitive to turf trespassers. The attitude I have seen is that since "MS" is not considered as a fatal condition, there can be no off-label or experimental treatment for it. Basically the "MS" group of patiemts is seen as a gravy train for the drug/research medico-industrial complex. It is not meddled with, without all i's dotted, t's crossed, all three phases of trials, and approval by the FDA and Health Canada. If I could find such an oncologist or anybody willing to administer some kind of EVB targeted therapy, it would likely be in the US, and cost me a lot of money, even though I am supposedly insured. I could not only be playing guitar, I could be driving to the six-figure job I had, but the insurance company won't move without the medical mafia's approval.

...

There are those who are shot and killed in the hours before an armistice comes into force.
I am afraid this is not only true for Canada, I am currently finding out the hard way that this is probably true in most places in Europe as well.
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Re: EBV targeting treatment yields clinical improvements in

Post by CureOrBust »

Good news. He has the funding and approval and will be starting the trial "soon". It is registered at:
https://www.anzctr.org.au/Trial/Registr ... eview=true
Where further details on the trial design can be read.
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Re: EBV targeting treatment yields clinical improvements in

Post by Scott1 »

Hi,

Don't forget Pender specifically mentioned Valacyclovir as a possible treatment route in the absence of a vaccine or monoclonal antibody. But... if you think only doing one thing is an answer, think again.

Regards
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Re: EBV targeting treatment yields clinical improvements in

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Scott1 wrote:Don't forget Pender specifically mentioned Valacyclovir as a possible treatment route in the absence of a vaccine or monoclonal antibody. But... if you think only doing one thing is an answer, think again.
Have you got any links to that "mention" of Valacyclovir?
I noticed these two links which have him talking near/with the Charcot guys. But they are specifically testing Raltegravir
http://multiple-sclerosis-research.blog ... ender.html
http://multiple-sclerosis-research.blog ... -your.html
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Re: EBV targeting treatment yields clinical improvements in

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Hi,

If you go to this link for the article he wrote that caused a stir - http://www.nature.com/cti/journal/v3/n1 ... 01425a.pdf and down load it as a PDF, he talks about it on page 7 under treatments. You may have missed it because of different spelling -there seem to be many versions. Here it talks about acyclovir but that is the converted state in the body. You would ingest it as valaciclovir which breaks down to Valine and aciclovir. (I do prefer it with a 'y'.)
His view was it only works in certain circumstances as the virus is both lytic and latent. It may have suited the article to say it that way. In the lytic cycle the cell bursts and many daughter cells are created. In the latent replication the cell divides. In each case there is window when the RNA ribbon is momentarily exposed so if valacyclovir is present it will insert a stop in the codan of the ribbon and halt replication.
Pender used two studies but both would be short term in my view. I don't know how the dosages were determined either. I've lost track of where I read it but somewhere in PubMed there is a mathematical model that concludes it would take Valacyclovir 11.3 years to clear EBV. Having pursued that route, I think it might take longer but the benefit was obvious in the short term for me. Of course, everyone will have their own metabolic state so it might take longer for someone else and it is clearly a very long term strategy.
Regards
Last edited by Scott1 on Wed Nov 04, 2015 1:13 pm, edited 1 time in total.
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