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Immunotherapy for PML: two case reports using IL-7 and experimental recombinant JCV VP1 protein therapeutic vaccination

Gareth Hardy, HIV i-Base

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection in the brain that is caused by JC polyomavirus (JCV) and associated with profound immunodeficiency. At present there is no antiviral drug for use against JCV and the options to treat PML are limited to restoring protective immunity.

In light of this Maria Sospedra and colleagues at the Institute for Neuroimmunology and Clinical MS Research, University Medical Center Hamburg-Eppendorf, detail two case reports where they attempted experimental treatment of PML with a novel immunotherapeutic approach combining vaccination and IL-7, in the September issue of Clinical Infectious Diseases. [1]

Both PML patients were HIV negative and suffered from either an acquired or a hereditary immunodeficiency. In both cases, significant clinical deterioration during the 12 months between diagnosis and experimental treatment was reported, and during this period JCV DNA remained positive in cerebrospinal fluid (CSF).

The experimental treatment consisted of: three subcutaneous injections of recombinant human IL -7, 10 ug/kg body weight, with approximately 7 day intervals between each; three subcutaneous injections of a therapeutic vaccine, recombinant JCV VP1 protein, 1 mg, administered two days after the first dose of IL-7 and then approximately two weeks later and finally after another four weeks; imiquimod cream [a TLR7/8 agonist] was administered topically as adjuvant, at the subcutaneous injection site at the time of vaccination.

The treatment was well tolerated by both patients. Substantial reductions in CSF JCV DNA viral load occurred following treatment in both patients. While no new T2 brain lesions were observed following the treatment when assessed by MRI, the researchers noted a subtle gadolinium-enhancing MRI lesion in patient 1, and an enhancement in patient 2, indicative of an immune response to the PML lesions. Both patients experienced significant clinical improvement of neurological symptoms following treatment. Scripps neurological rating scale [SNRS] score for patient 1 improved from 71 one month before treatment, to 80 12 months afterwards. Patient 2 improved from 49 one month before treatment to 53 by 14 months after treatment and had signs of mild neuropsychological improvement regarding alertness.

JCV VP1 antigen-specific CD4 T cell proliferative responses were determined with both thymidine incorporation assays and CFSE dye-dilution assays by flow cytometery. Prior to therapy, no VP1-specific T cell responses were observed. After 84 days, both patients exhibited robust positive proliferative T cell responses to VP1, largely attributed to memory CD4 T cells by CFSE flow cytometery assays, although there were some CD8 T cell responses also. Tetanus toxoid antigen proliferative responses also improved in both patients, probably because of the immune-restorative effects of IL-7.

The authors conclude that this treatment was well tolerated, and appeared to have long-lasting efficacy by eliminating JCV viral load in CSF, inducing MRI-proven inflammation at sites of PML lesions without causing immune restoration inflammatory syndrome [IRIS] and by causing clinical stabilisation and slight improvement. Importantly, the authors suggest in their discussion that this approach is NOT suitable for people with HIV. This is most likely because rapid immune reconstitution with ART has been shown to paradoxically worsen PML or induce its onset [2].

Therefore the anticipated risk of IRIS-aggravated PML in HIV positive patients may be much greater than in people with other forms of immunodeficiency. Despite this, the authors suggest prophylactic vaccination with VP1 may be of benefit to HIV positive people, before starting ART. Further studies would need to investigate this.

Comment

We sought clarification from the corresponding author of this paper, as to why they deemed the approach inappropriate for persons with HIV infection.

They confirmed that while the approach should in principle be applicable to all PML cases, they urge caution in respect to people with HIV because immune restoration with ART should be attempted first in order to try and avoid fulminant IRIS. There is a chance that this immunotherapy in patients with IRIS-PML could further inflame immune-reconstitution mediated damage.

Dr Nicholas Davies, Consultant Neurologist at Chelsea and Westminster Hospital, London, adds that the approach may however prove useful in patients with poor immune reconstitution and little or no IRIS. In addition, the authors’ suggestion of a JCV therapeutic vaccine may prove very useful for patients potentially facing immunosuppression.

References:

  1. Sospedra M et al. Treating progressive multifocal leukoencephalopathy with interleukin 7 and vaccination with JC Virus capsid protein VP1. Clin Infect Dis (published 11 September 2014), 10.1093/cid/ciu682.
    http://cid.oxfordjournals.org/content/early/2014/09/12/cid.ciu682.abstract?papetoc
  2. Cinque P et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J. NeuroVirol (2001), 7: 358 – 363
    http://www.jneurovirol.com/pdf/7%284%29/358-363.pdf

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