Wednesday, 26 April 2017

AAN Targeting EBV with CD8 specific T cells

Symptomatic and Objective Clinical Improvement in Progressive Multiple Sclerosis Patients Treated with Autologous Epstein-Barr Virus-specific T Cell Therapy: Interim Results of a Phase I Trial

Michael Pender, MD, PhD; Peter Csurhes; Corey Smith; Nanette Douglas; Michelle Neller, PhD; Leone Beagley, PhD; Sweera Rehan, PhD; Tracey Hopkins, PhD; Kate Thompson, PhD; Stefan Blum, MD; Kerryn Green, MBBS; Zara Ioannides, MD; Alan Coulthard, PhD; Kaye Hooper, PhD; Scott Burrows, PhD; Rajiv Khanna, PhD

Objective: To determine the safety of treating progressive multiple sclerosis (MS) patients with autologous Epstein–Barr virus (EBV)-specific T cells. Background: Mounting evidence indicates a role for EBV in MS pathogenesis. EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T-cell immunity.
Design/Methods: In this trial we administer autologous EBV-specific T cells to patients with progressive MS (EDSS 5.0–8.0). Each patient receives their own T cells stimulated ex vivo to enhance reactivity to EBV nuclear antigen-1, latent membrane protein 1 (LMP1) and LMP2A, and is followed through 26 weeks. Four escalating dose infusions are administered biweekly.
Results: To date, four SPMS patients and one PPMS patient have been treated. No significant adverse events have been observed. Three patients experienced symptomatic and objective clinical improvement, which commenced 2–8 weeks after the first infusion and was most marked in the two patients receiving T cells with the highest EBV reactivity. Striking improvement occurred in one SPMS patient, with normalization of lower extremity tone and plantar (Babinski) responses for the first time in 16 years, increased walking distance with walker from 100 metres at baseline and for the previous 5 years to 1200 metres, marked reduction in fatigue, increased manual dexterity, and improvements in lower extremity power, reflexes and sensation. A second SPMS patient had reduced fatigue, increased productivity and improved balance. The third responder (PPMS) had improved colour vision, visual acuity and manual dexterity and reduced fatigue, lower extremity spasms and urinary urgency. These data are consistent with prior data from the first patient ever treated (SPMS compassionate use) who experienced reduced fatigue and lower extremity spasms, and improved cognition, hand function and productivity.
Conclusions: This is the first report of clinical improvement in a prospective trial of autologous EBV-specific T cells to treat progressive MS patients. Further studies are planned.

Study Supported By: Multiple Sclerosis Society of Queensland, Multiple Sclerosis Research Australia and Perpetual Trustee Company Limited


This isa safety study designed to test whether vaccination against EBV could impact on MS. They have made viral reactive CD8 T cells and transfer them in to kill the EBV infected (B) cells. This will be of interest, so maybe ProfG may have time to tweet or report on the presentation.


In the AAN press release it said the trial was designed to look at ten people and have found it should have been five with PPMS and five with SPMS. In the trial, the volunteers received four escalating doses of cytotoxic CD8 T cells over six weeks and were followed for an additional twenty weeks after the last dose. 

Here the abstract above it says five people were looked but in the press release from the AAN, it says six. These results are encouraging, but the study is seemingly unblinded and is reporting symptomatic improvements and this is not what a trial in progression may go for. But being a phase I it is designed to say it is safe. 

This study used autologous cells, so they were generated from the same people who they were later received the cells back after they were expanded. 

However, this data is now being reported as company data. It appears the company has got some rights from the University in Queensland. 

Anyway according to the company website. They are planning to use their product as allogenic cells, i.e. made in one person to be used in another person. Whilst this will help in production of a standardised cell this, without more data on the technology, makes little immunological sense as to get proper engagement of cells you need your antigen presenting cells to present to your own T cells.

An allogenic cell may not recognize the B cells infected with EBV in another person, but they can recognize a large percentage of other peoples major histocompatibility complexes (transplantation antigens) as a target, so you could be injecting cells that that can potential kill every cell in the recipient. I hope not. 

More likely the injected cells will last about 5 days and then the recipient will destroy them as being invaders.  

20 comments:

  1. Doesn't this prove conclusively EBV is cause of MS? If progressive patients, currently untreatable, can be treated using this method of targeting b infected cells. Why wait to start phase 3 trials? Patients need treatments now not in 15 years.

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    1. Good luck, but ProfB explained some of the caveats being too gung-ho about such intervention. More data please.

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  2. Yes. Agree with you whole heartdley. But we are already taking unacceptable risks that dampen a patients immune system. We are already taking medications that had unacceptable risk profile for other conditions. Ocrelizumab killed patients on the arthritis trial so Was switched to ms where risk appetite was greater. Not such wonder drug? Alemtuzumab kills all immune cells? And team g is worried about the effects b cell depleting therapy targeting only b cells infected by EBV? Hmmm...ps not to forget HSCT in phase 3 trials? MS patient safety ? I say bring it on. Can't be worse than what's already out there. Besides it's m.a.b. body will rebalance.

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    1. There are interventions which, for all we know, are relatively low risk, but unlicensed: http://onlinelibrary.ectrims-congress.eu/ectrims/2016/32nd/145845/cesar.alvarez-gonzalez.treating.multiple.sclerosis.with.generic.cladribine.html

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  3. This is good news, I guess.
    I hear for a long time on this blog that there should be a correlation between EBV and MS. This could be going in the right direction.
    Is there a trial planned for the RR-MS too?

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    1. In the hands of a company: http://www.atarabio.com/

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  4. It is nice to see how this project has developed since 2014! Please continue like this as it gives us hope hhttp://www.msdiscovery.org/news/news_briefs/9705-exploiting-ebv-ms-link-quell-secondary-progressive-disease

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  5. I think this is great news - I remember some years ago reading about this 1 patient starting to walk again and thought this is never going to happen so soon and now we've got a trial, however small.

    Congrats to Prof Pender and team.

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    1. My point exactly. SINCE 2014. The whole point of doing these trials in the so called gold standard is to make drug development so expensive so any drug discovery by any small company will be forced to partner with a large pharma. Therefore enforcing a monopoly. And ensuring high drug prices. As ex Chemical engineeer working first for pharma on drug trials I've seen this first. Even universities are controlled through post doc research grants, sponsorships etc. FDA cures act is move in the right direction.

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  6. This is potentially huge. Could it be MS's silver bullet? Maybe the next major advance after DAA in HCV infection is EBV-specific T cells to MS. Shame they are moving away from autologous T cells though. Anyway, onto Phase 2+!

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    1. Not a shame not using autologous...it is bonkers

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    2. Apparently not only logistics..but effectiveness is a factor.

      "An alternative approach which has recently been explored is the use of allogeneic DC as vaccine vehicles. A major advantage of the use of alloDC is the feasibility of preparing large clinical-grade batches that may be used for all patients, thus providing a more standardized DC vaccine in terms of phenotype and maturation status. As with allogeneic tumor cell-based vaccines, bypassing the need for individually prepared vaccines represents a considerable logistic advantage. Although seemingly counter-intuitive, from a theoretical point of view alloDC-based vaccines might even induce a stronger vaccine-specific immune response than autoDC [13]. Since an estimated 1–10% of the circulating T cell repertoire is directed against allo-antigens, alloDC may be expected to trigger a broadly reactive T-cell response.."

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491427/
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181031/

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    3. "Not a shame not using autologous...it is bonkers"

      Apparently they are developing both versions.

      "We look forward to additional development with both the autologous and allogeneic versions of ATA188 to further evaluate the potential therapeutic utility of targeting EBV in the treatment of MS."
      http://investors.atarabio.com/releasedetail.cfm?ReleaseID=1022221

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    4. I agree with adam that allogenic cells are easier to develop as a therapeutic to industry standards ,but in contrast to dendritic cells the CD8 T cell is an effector killing machince.

      As you say "since an estimated 1–10% of the circulating T cell repertoire is directed against allo-antigens" they are there to kill allogeneic tissues.

      However based on the company website this approach is in trial

      Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

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  7. Do they know if they eliminated EBV driven B cells completely in this small study or is ongoing therapy necessary? Why only SPMS and PPMS patients chosen? Shouldn't it work even better on RRMS before all the damage is endured by the patient? By what mechanism does this help progressive MS patients, i.e. remove APC, dampen hot microglia or astrocytes, stop apoptosis/Ca influx? Why would progressive patients get improvements? Endogenous remyelination?

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  8. Anyway good news!!!
    This EBV sucks...

    Perhaps the study has started looking at progressive MS to show that if it can do effect against PP and SP it will probably make the RR the same positive combat effect, and/or even stop the disease from time to time.
    And even because the first treatments for progressive MS are emerging now, ie there is a still unmet need for actual treatment.

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  9. This is likely going to be one of the most important areas of MS research in the next few years. In looking back at what we know now, many dots have been connected concerning EBV. Likely we'll see more dots connected as the research advances. Some of the connections that have been made certainly help to explain why certain existing DMT therapies have been moderately successful, especially ones that target B cells at some level.

    I believe that progressive MS was looked at in this study because there is a bit clearer path available to test the theory--to see if B cells are targets that contain some level of EBV would result in some physical improvement that could be measured. This might be a little more difficult to demonstrate with RRMS, especially in a relatively short time frame.

    If EBV were attaching itself to B cells, it's likely that the number of infected B cells would come and go over time as a typical immune system would reduce (through T cells) some level of the infected B cells. One of the things the few test subjects experienced in this study is a fairly noticeable change in levels of fatigue. It's possible that these subjects were previously experience some level of an active infection where their immune system was constantly working in overdrive. Once the "trained" T cells were introduced the level of infected B cells were decreased and thus it's possible that the immune system could then relax a little and in turn symptoms would noticeably decrease.

    I think the very big (no huge!) challenge here will be in how to monetize this type of targeted therapy. It certainly makes the shotgun, one size fits all approach of killing off lots of B cells kind of old school. If this much more targeted approach of attacking only infected B cells really continues to show promise then it kind of throws the existing multi-billion dollar drug industry out the window.

    In the end, this is a great story. The patient who has MS possibly has everything within they need to fight this menace. They just need to retrain their T cells a little so that they can do their magic.

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  10. Can ProfG. comment about this research?

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  11. Missed this post until now. This is really, really exciting.

    Wow, just wow. And I'm a super-cynical PPMSer.

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  12. What proportion of an MSer's B-cells are infected with EBV, i.e. what proportion would be destroyed by the EBV-specific T-cells?

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