Generalised EBV vaccine a step closer?


EPO2229 – Preliminary phase 1 safety of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus (EBV)-targeted T-cell immunotherapy for patients with progressive multiple sclerosis (MS)

Background and aims

Epidemiological and serological evidence suggest EBV infection is associated with MS pathogenesis. Previously, we showed that treatment with an autologous EBV-targeted T-cell immunotherapy in 10 patients with progressive MS may prevent MS progression and improve clinical symptoms. This study evaluates safety and feasibility of monotherapy with pre-manufactured, unrelated donor (off-the-shelf, allogeneic) EBV-targeted T cells (ATA188) for adults with progressive MS.Methods

A phase 1 multicentre, open-label, single-arm, 2-population, dose-escalation study enrolled EBV-seropositive adults with primary/secondary progressive MS (NCT03283826). Cohorts 1-4 receive 5.0×106, 1.0×107, 2.0×107, and 4.0×107 cells, respectively, on days 1, 8, and 15 in 2 cycles. Plasma inflammatory biomarkers (IL-2, IL-1β, TNF-α, IL-6) are monitored throughout treatment.Results

By 7 January 2019, 6 participants in cohort 1 (mean age: 58.2 years; 50% female) and 6 participants in cohort 2 (mean age: 56.7 years; 83% female) have received ≥1 dose. No dose-limiting toxicities or serious or grade ≥3 treatment-emergent adverse events (TEAEs) were reported. TEAEs occurred in 58% (7/12) participants (4/6 in cohort 1 and 3/6 in cohort 2); all TEAEs were grade 1 (17%) or grade 2 (42%). Most common TEAEs (n=2) were rhinorrhoea, fall, contusion, and headache. Two participants reported possibly-related grade 2 TEAEs. In cohort 1, 3 participants experienced upper respiratory infection symptoms, with 2 developing symptoms 2-5 months after treatment. Inflammatory cytokines remained at or near baseline throughout treatment.

ConclusionInitial safety data indicate ATA188 is well tolerated by adults with progressive MS and support proceeding with the study and identification of recommended phase 2 dose.

In this vaccine they take CD8 T cells that are responsive to Epstein Barr Virus. They spot virally infected cells and kill them. This is not news they have done this already. There they took the individual cells made the antiviral cells and then injected them. Personalised medicine. However in this case they are made by some one else. These are termed allogeneic cells.

This makes it easier to make as a produce as one cell can be mass produced allowing for better quality control and more of a pharmaceutical product and so it may be one cell may be suitable for many different people.

This study says they are safe. Immunologically I do not really buy this approach. I am sure they an matched for important transplantation antigens so they will work, but the cells will be different and so rejectable but the immune system of the recipient. Next and more worrying is that the the cells may be able to reject the the person they are going into.

A theorectical poosibility that I hope doesn’t happen. But if it does it will be a case of I told you so.

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  • I’m not an immunologist, but isn’t a vaccine something you give to expose someone’s immune system to an antigen that would hopefully prevent an infection. This sounds more like EBV-targeted cell therapy rather than a generalized EBV vaccine. I would appreciate an explanation of this nuance?

  • I am in the ATA188 trial, in the second highest dosing (not sure how many cohorts there are, but I’m the second last).

    I asked if the cells reproduce or die off, and my understanding from what I was told, is that the cells are not expected to survive. I have been told they only survive for 3 days. When I asked if that was their half-life or the point at which they could not be detected, I couldn’t get a answer. So, rejection is only an issue if it is less than their expected 3 days, and is also something they have designed for, and would of experienced in their previous trial.

    Another interesting piece of information I got was that they have videos that each cell kills 1 EBV every 6 seconds (I think I got 20 million cells in 3 doses from memory).

    • Thanks for this information, very informative. I remember a study done by the US Navy, they grew millions of anti-viral (CMV) CD8 T cells which were Fas CD95 positive as most activated cells are, it took them months to grow enough cells, they injected them and they were all dead within 24 hour as the Fas Ligand in the body induced the cells to commit suicide. Maybe this is happening here. Maybe rejection. However if they are only around for 3 days is that long enough for them to do their bit?. Or is this the marketing strategy to keep people coming back.

      Hope it works
      Best wishes

      • Read their previous results for the post chemo treatment, they were outstanding. Just going off a vague memory from over a year ago, they went from an expected patient survival rate of 1 in 10 to a death rate of 1 in 10. This is not their first EBV rodeo.

        I think the idea is that they kill off the EBV currently present, and it then has a 12 month re-dose to kill ’em when they repopulate. As for marketing, the 3-day die-off was an unpublished detail that I only found out when I explicitly asked. I think the trial (although this one is open-label), will hopefully separate marketing from science.

        It would be great if they lived on and divided and multiplied (and hence I asked), but they are obviously expecting a big reduction of EBV load by the dosing, to be effective enough as a treatment in itself, which needs to be repeated.

        FYI: I am not sold on the results just yet. My walking, Ataxia & balance have not improved; which is what i really care about (I think it actually got considerably worse a few hours after a dose, and then i recovered by the next day). However, I think the paresthesia in my hands is notably reduced, and thinking about it now, it is still slowly reducing (3 weeks since last dose).

        PPS: For clarity, I meant 20M cells in each of the three individual doses (ie 60M in total), not divided over the 3 doses.

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