Treating carry-over PML after immunodepletion

Treating PML in the presence of immunodepletion is not necessarily a death sentence. There are some solutions on the horizon. 

At present we don’t have an anti-viral agent that works against the JC virus that causes PML (progressive multifocal leukoencephalopathy). Therefore we have to rely on your own immune system to fight and clear the virus if you develop PML. This is why we wash out natalizumab with plasma exchange or stop the immunosuppressive when somebody develops PML. A problem arises when we can’t reconstitute CNS immunosurveillance or your immune system. The latter can happen with IRTs (immune reconstitution treatments) and potentially with anti-CD20 therapies (they do reduce CD8+ T-cells as well) or in people with persistent lymphopenia post fingolimod or dimethyl fumarate or other DMTs for that matter. This is where immunotherapies are needed.

One strategy is to give unfortunate people with PML in this situation donor anti-JCV lymphocytes that are matched to their HLA (human leukocyte antigens) to fight the infection. In short, this is an immune transplant, i.e. giving them donor-matched T-lymphocytes to fight JCV. The study below uses T-cells that were designed to attack the BK virus a virus that is very similar to JCV.

The logistics of immunotherapy for PML are not insignificant and ideally need to be established before hand so as not to delay treatment. One option is to rely on Pharma to create a bank of HLA-specific cytotoxic T-lymphocytes that are frozen and cane be mobilised within 24-48 hours as a licensed treatment for PML.

When I was at the NIH earlier this year I heard about such a trial and would urge you to contact them if and when the need arises.

Muftuoglu et al. Allogeneic BK Virus-Specific T Cells for Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2018 Oct 11;379(15):1443-1451. doi: 10.1056/NEJMoa1801540.

JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo-expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus-specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; number, NCT02479698 .).

CoI: multiple

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