T cell vaccination study: double-blind and controlled!

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#MSBlog: A first for the T-cell vaccination lobby; a double-blind controlled trial! Time for a celebration?

Epub: Karussis et al. T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial. PLoS One. 2012;7(12):e50478. doi: 10.1371/journal.pone.0050478. Epub 2012 Dec 14.

BACKGROUND: T-cell vaccination (TCV) for MS refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. Previously published clinical trials have been all open-labeled.


AIM: To evaluate the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial.

METHODOLOGY: 26 relapsing-progressive MSers were enrolled in the study (mean age: 39±9.8 years; mean EDSS: 4.4±1.7). T-cell lines reactive to 9 different peptides of the myelin antigens, MBP, MOG and PLP were raised from the MSers’ peripheral blood. The MSers were randomized into two groups: 19 were treated with TCV (four subcutaneous injections of 10-30×10(6) T-cells, attenuated by irradiation, on days 1, 30, 90 and 180) and 7 MSers were treated with sham injections. Twenty-four MSers (17 in the TCV group and 7 in the placebo) were eligible for per-protocol analysis.

RESULTS: At one year following the inclusion, an increase in the EDSS (+0.50) and an increase in 10-meter walking time (+0.18 sec), were observed in the placebo group; in the TCV group there was a decrease in the EDSS (-0.44; p<0.01) and in the 10-meter walking time (0.84 sec; p<0.005). Sixteen of the 17 MSers (94.1%) in the TCV group remained relapse-free during the year of the study, as compared to 42.9% in the placebo group (p = 0.01 and p = 0.03 with adjustment). The proportion of MSers with any relapse during the year of the study in the TCV-group, was reduced by 89.6%., as compared to the placebo-treated group. MRI parameters did not change significantly.

CONCLUSIONS: This is the first controlled, double-blind trial with TCV in progressive MS. The results demonstrate the feasibility and safety of the procedure, and provide significant indications of clinical efficacy. Further studies with larger groups of subjects are warranted.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01448252.

T-cell

“The results of this study are a first, i.e. the first double-blind, controlled clinical trial of T cell vaccination in MS and they are positive. What is T-cell vaccination? The investigators’ take T cells from the blood of MSers and then expand their numbers, i.e. grow them in the lab, by stimulating them with putative autoantigens. They then irradiate them to stop them dividing and then inject them back into the blood stream of the MSer. The idea is that the immune system sees these cells as foreign and mount an immune attack against them. By doing this the immune system then destroys other autoreactive cells. Is sounds simple, but the immune system usually bounces back with new T cells that have not been included in the vaccine pool.”

“I don’t want to spoil the party, but I doubt this approach will work. Firstly, it is based on the premise that MS is an autoimmune disease. I have argued before that I don’t think MS is autoimmune. The target antigens are MBP, MOG and PLP; why these antigens? These antigens are immunogenic in animals and induce EAE, but the evidence that they play a role in MS is circumstantial. In fact the auto-antigen in MS remains undefined. Finally,  this study is very small and underpowered. Therefore the the odds are the results are likely to be a false-positive. Let’s hope I am wrong and that a larger follow-on study is done!”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

12 comments

Leave a Reply to Vasilis Vasilopoulos Cancel reply

  • Lovin the feedback buttons, thanks! Happy New Year Team G. I really appreciate your work here! (Even if you're kind of a buzz kill on the T-cell vaccine research.)

    • Prof G may argue that the immune treatments that work are treatments that get rid of B cells, which is a reservoir for Epstein Barr Virus..get rid of B cells get rid of virus.

      VV may argue that immune treatments do nothing, which is counter to the reality

      Maybe prof G is wrong and there is an autoimmune component.. keepan open mind,

    • Suppress the immune system and there will be less CNS inflammation, therefore less pressure to the area of damaged tissue, therefore a self-perceived improvement and less evident MRI lesions. This is what treatments do. Nothing more. The disease keeps destroying tissue in the background.

    • A good analogy is viral hepatitis; the immune response to the virus causes the damage. Without an immune response the liver does okay. A god analogy is tropical spastic paraparesis or HTLV-1 associate myelopathy (HAM_; before it was shown that a virus causes the disease it was considered autoimmune. In fact, most people with HAM were diagnosed with a PPMS before the virus was discovered. So please watch this space.

  • Maren, it depends on how you define "work". So far, no DMT has been able to stop progression. The only "benefit" has been a purported reduction of mean annualised relapse rate in groups of people tested by the manufacturers of the DMTs in so called "clinical trials".

    • Tzartos JS, Khan G, Vossenkamper A, Cruz-Sadaba M, Lonardi S, Sefia E, Meager A, Elia A, Middeldorp JM, Clemens M, Farrell PJ, Giovannoni G, Meier UC. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology. 2012 Jan 3;78(1):15-23. doi: 10.1212/WNL.0b013e31823ed057. Epub 2011 Dec 7.

      OBJECTIVE: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain.

      METHODS: White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization.

      RESULTS: We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro.

      CONCLUSION: These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.

    • "We therefore additionally used a very sensitive real-time PCR (Stevens et al., 2005a) and reverse transcription–PCR method (Stevens et al., 2005b) to search for EBV genomes and encoded RNAs, respectively, in five tissue blocks containing B cell-rich areas from three patients. Using this method, one positive cell in 100 000 cells can be detected. None of the multiple sclerosis tissues examined revealed the presence of EBV DNA or RNA while all EBV-associated tumour samples and the EBV-positive cell line JY (1/100 000) were all positive."

      You co-authored the above statement. As a reader i'm confused, because according to you:
      1. EBV lives in B-cells.
      2. EBV is not to be found in B-cell rich areas.

    • As for the EBERs in active lesions, they could very well appear after the death of oligodendrocytes (you say they were mostly perivascular). You should disprove this before drawing conclusions. After all, the only available data of early lesions in the brain and the spinal cord show ABSENCE of infiltrates, but already dead oligos.

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