It seems this is PML week. first PML on alemtuzumab and now this….a treatment for PML or is that that Two
I first thought wow….but then I read the title and I thought that maybe I’m being a bit thick here because I have seen a few people wetting their pants on twitter with excitement on this news, but maybe I am missing something?
You have a disease that causes white blood cells to create an inflammatory environment that destroys oligodendrocytes (myelin-forming cells), creating an environment for symptoms for loss of nervous control and leads to devastating damage. This is called MS (multiple sclerosis).
You stop the white blood cells entering the brain and so they can’t cause damage to the oligodendrocyte and attacks stop. This is called PROGRESS.
There is a virus called the John Cunningham (JC not to be confused with Jesus Christ:-) Virus and this has no treatment, unless you believe teriflunomide is anti-viral:-). This is called a NUISSANCE.
However 50% of us have the JC virus that lives in the bone marrow and the drugs stopping relapse in MS can cause cells harbouring the virus to end up in the circulation and some get into the brain. This is called a ticking TIME BOMB
The virus gets in the brain and infects and destroys oligodendrocytes and you get devastating damage that either kills you (25% of the time) or leaves you quite disabled. This is called PML (Progressive multifocal leukoencephalopathy).
Next you spot PML and stop the MS treatment or you don’t notice a subclinical infection. when you switch the MS drug and this allows the immune system back into the CNS. The T cells are anti-viral cells that are allowed back in the brain and kill virally infected oligodendrocytes. You get devastating damage that can lead to accumulation of disability. This is called IRIS (Immune reconstitution Inflammatory syndrome).
Now you take a drug that is called an “immune checkpoint” inhibitor that is used in cancer to boost the immune system so that it is better able to detect and kill cancer, but gives the problem of unwanted autoimmunity as you boost the immune system and it can damage you cells. This is called a side-effect but you are happy that you get rid of the cancer so you are still around.
The immune check point says stop and halts the further activation of the immune system. There are a few one is called PD-1 (programmed death 1) and others include CTLA4.
So in this study they have used an immune-checkpoint inhibitor and this now says to the immune system “Go, Go Go”. In this study they have given people with MS the check point inhibitor when they have developed PML. So the signal you get is “GO, GO GO” to race into the CNS and kill the infected oligodendrocytes I mean killnthe virus so you can get IRIS and could cause damage. You may be around to thank your neuros for saving you, but at what cost. This is hailed as PROGRESS.
Whilst I am sure if you are in the scary position of developing PML, this news is a welcome addition, however whilst patting ourselves on the back for a job well done, surely we need to focus on finding a treatment for the virus that does not kill the infected host cell, so that we can get rid of the virus without the IRIS
In this study the people with PML had PD-1 on there surface this is a negative regulator of immune function by giving antibodies to block this there was some rejuvination of the immune response and the viral levels dropped. They say that IRIS was not induced except in the case on one person, maybe someone will explain this to me, it is suggested that it is because there is lymphopenia (low T cell counts), but how do you clear virus from the brain, without getting into the brain to clear it.
Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy.Cortese I, Muranski P, Enose-Akahata Y, Ha SK, Smith B, Monaco M, Ryschkewitsch C, Major EO, Ohayon J, Schindler MK, Beck E, Reoma LB, Jacobson S, Reich DS, Nath A.N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1815039. [Epub ahead of print]
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection that is caused by the JC virus and is typically fatal unless immune function can be restored. Programmed cell death protein 1 (PD-1) is a negative regulator of the immune response that may contribute to impaired viral clearance. Whether PD-1 blockade with pembrolizumab could reinvigorate anti-JC virus immune activity in patients with PML was unknown.
METHODS: We administered pembrolizumab at a dose of 2 mg per kilogram of body weight every 4 to 6 weeks to eight adults with PML, each with a different underlying predisposing condition. Each patient received at least one dose but no more than three doses.
RESULTS: Pembrolizumab induced down-regulation of PD-1 expression on lymphocytes in peripheral blood and in cerebrospinal fluid (CSF) in all eight patients. Five patients had clinical improvement or stabilization of PML accompanied by a reduction in the JC viral load in the CSF and an increase in in vitro CD4+ and CD8+ anti-JC virus activity. In the other three patients, no meaningful change was observed in the viral load or in the magnitude of antiviral cellular immune response, and there was no clinical improvement.
CONCLUSIONS: Our findings are consistent with the hypothesis that in some patients with PML, pembrolizumab reduces JC viral load and increases CD4+ and CD8+ activity against the JC virus; clinical improvement or stabilization occurred in five of the eight patients who received pembrolizumab. Further study of immune checkpoint inhibitors in the treatment of PML is warranted. (Funded by the National Institutes of Health.).
However treatments for PML are just like buses and two come at once. In this study there were low T cell counts and PD-1 inhibition with Nivolumab increased CD4 T cells. The neurologic signs stabilised. The was brain atrophy
Treatment of Progressive Multifocal Leukoencephalopathy with Nivolumab.Walter O, Treiner E, Bonneville F, Mengelle C, Vergez F, Lerebours F, Delobel P, Liblau R, Martin-Blondel G; Immune Checkpoint Inhibitors in PML Study Group. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1816198. [Epub ahead of print]