EBV Immunotherapy Works in MS

E
Perhaps this is what we have been hoping for, but come on I say, look at the result. It is hardly the end of MS.

Pender MP, Csurhes PA, Smith C, Douglas NL, Neller MA, Matthews KK, Beagley L, Rehan S, Crooks P, Hopkins TJ, Blum S, Green KA, Ioannides ZA, Swayne A, Aftab BT, Hooper KD, Burrows SR, Thompson KM, Coulthard A, Khanna R. JCI Insight. 2018; 3. pii: 124714


BACKGROUND:

Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.

METHODS:

An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.

RESULTS:

Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test).

CONCLUSION:

EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.



We have been building up the idea that EBV activity is pivotal in the development of MS. Therefore, there have been clear pleas that we get on and make EBV vaccines and MS will go away.

This study looks at the effect of transferring EBV specific CD8 T cells into MS. Therefore, it is a type of vaccine.


Hurray, You say. 

However, I say we have to look at the results. It is clearly not a cure, notably in the people with strong responses. 

There are claims that it effects some symptoms. How is it working?

It’s open access so you can read it.

Well done to Prof Pender for getting off the ground and there are benefits reported however.

It is suggested that there is an effect on fatigue. This could be due to an anti-inflammatory effect, but it is not that compelling.

The median Fatigue Severity
Scale score  for the combined group of 10 treated patients was lower at week 27 than at week 1 (P = 0.0547). 



Yes this means there was NO difference the null hypothesis that there is no difference is accepted.. 

CSF IgG analysis was performed before and after T cell therapy in 9 patients. The CSF IgG index and intrathecal IgG synthesis had decreased at week
27 compared with baseline in 4 of the 9 patients (participants 1, 6, 9, and 13), 3 of whom showed neurological
improvement (participants 1, 9, and 13). There was no detectable change in the pattern of CSF oligoclonal
IgG bands after T cell therapy. Notably, in participant 9, whom we first treated with EBV-specific T
cell therapy in 2013 and treated again in 2017 in this trial, the CSF IgG index and intrathecal IgG synthesis
decreased after the first course of treatment in association with clinical improvement, increased 3.5
years after treatment in association with worsening symptoms, and again decreased after retreatment, in
association with clinical improvement.

We have to remember this is a safety study and this shows that the treatment is safe. The people in the trial had progression and we know that this is not the best population to show immunomodulatory effects. 


Anyway the approach is not dead and we will see more on this approach. Have a read and see what you think.


If the Glass Half Full ProfG did this you may have a more positive spin. A company is now taking the lead. However, I fear that they are making a mistake not using autologous cells (i.e from the person who is going to recieve the cells) , but allogeneic made from someone else. Immunology theory thrown out of the window, even if there is a major HLA match, there will be significant mismatch.

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MouseDoctor

15 comments

    • Acyclovir is a common anti-Herpes treatment that is used in peole treated with alemtuzumab for example . At least 50% relapse

      Aciclovir is converted by viral thymidine kinase to aciclovir monophosphate, which is then converted by host cell kinases to aciclovir triphosphate (ACV-TP). ACV-TP, in turn, competitively inhibits and inactivates Herpses simplex virus-specified DNA polymerases preventing further viral DNA synthesis .

      Combivir is a combination of two antiretroviral medications, lamivudine and zidovudine.

      They work by blocking the action of the enzyme, reverse transcriptase, that the virus requires to reproduce

      Lets hope this case report is replicated

    • Hi Mouse Doctor,

      I really appreciate you taking the time to answer my questions and explaining both drugs and their current usage.

      However, it's a bit like saying acyclovir cannot be used to treat MS because it is currently not used to treat MS. And at the same time you are telling me that MS can in theory be treated with antiviral drugs, such as drugs against EBV. And then you are telling me that acyclovir works against herpesvirus DNA polymerases. And it appears that EBV is a herpesvirus.

      So I am completely confused?

    • Like many viruses, EBV has both lytic and latent replication phases. In the lytic phase, EBV is making more viruses that will go and infect other cells. This is the phase against which aciclovir and prodrug forms of it are partially active. (Viral thymidine kinase is expressed during the lytic phase.) But EBV spends most of the time in its latent phase. It exists as its own circular chromosome with a select few viral genes being expressed and relying on the host cell DNA polymerases to replicate the DNA when the cells divide. So aciclovir is inactive against latent EBV.

      The epidemiological data suggesting a link between EBV and MS is quite strong. There is less (but growing) evidence demonstrating a physiological (biochemical) link between the two. Pender's paper is helping to bring people around to look more closely.

      • Hi,

        Seems my EBV (HHV-4) were not active: Tests, dated 2014:

        EPSTEIN-BARR VIRUS SERODIAGNOSIS

        Early markers
        – Anti-VCA IgG: 39.3 AI (Positive) Neg < 0.8
        – Anti-VCA IgM: < 0.2 IA (Negative) Neg < 0.8

        Late marker
        – Anti-EBNA IgG: 80.0 AI (Positive) Neg < 0.8

        Test for Ac-heterophiles (MNI TEST)
        – AC Heterophile IgM: < 0.2 AI (Negative) Neg Where is the virus to be found?

        1) EBV persists asymptomatically throughout life as a B-cell infection. The infection is mainly latent, but periodically reactivated EBV reproduces lytically in a subset of B cells.

        2) The “memory” T-cells remain in abnormally high numbers once the infection has passed. Over the years, they release chemokines molecules.

        Lots of theories …

        CCl: Is it worth testing my EBV again?

        Thanks+++
        Brgds!

    • To prevent infection in the first place (sterilizing vaccine), to treat IM (anti-viral) and to target MS with antivirals or immunotherapy that reduces viral loads (anti-CD20 followed by an antiviral).

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