Combined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy
A Case Report
Citation Manager Formats
Make Comment
See Comments

Abstract
Objective We report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML).
Results A 57-year-old male patient diagnosed with PML presented a fast-progressing right hemiparesis, aphasia, and cognitive deficits. Brain MRI showed a severe leukoencephalopathy with diffusion restriction. The patient was treated with 10 doses of pembrolizumab (2 mg/kg body weight) in differing intervals and 2 partially human leukocyte antigen-matched allogenic BK virus-specific T cell transfusions after the fifth pembrolizumab treatment. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. Moreover, the regression of leukoencephalopathy and disappearance of diffusion restriction in subsequent brain MRI were observed. The combined treatment resulted in a clinical stabilization with improvements of the cognitive and speech deficits.
Discussion This case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. Thus, the combined treatment of pembrolizumab and virus-specific T cells should be further evaluated as a treatment option for PML in future clinical trials.
Progressive multifocal leukoencephalopathy (PML) is a rare disease caused by the reactivation of JC virus in immunocompromised patients, often with poor outcome. There is no standard therapy, but case series showed promising results regarding 2 treatment options: In 2019, treatment with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab resulted in clinical stabilization, decrease in virus load, and no further progression in brain MRI in 5 of 8 patients with PML.1 PD-1 is an inducible surface receptor and negative regulator of T cell lytic function. In chronic viral infections, persistent exposure to viral antigens can result in permanent PD-1 expression and T cell exhaustion.2 It was hypothesized that pembrolizumab boosts antiviral activity by blocking the PD-1 pathway in otherwise dysfunctional T cells, suggesting that pembrolizumab treatment relies on pre-existing virus-specific T cells.3 In 2018, a small case series reported a favorable ouotcome in 2 of 3 patients with PML after treatment with allogenic BK virus-specific T cells from healthy donors.4 BK virus has a high sequence homology with JC virus, and consequently, these T cells expanded with a pool of BK peptides showed cross-reactivity with JC virus-derived peptides. In this case study, according to CARE guidelines,5 we report the results of the combined treatment with pembrolizumab and BK virus-specific T cells in a patient with PML.
Results
The 57-year-old male patient was in complete remission of stage IV nodal marginal zone lymphoma (nMZL; R-CHOP-21 treatment) diagnosed 4 years before PML onset. He presented with a mild right hemiparesis lasting 1 week. A brain MRI revealed multiple, diffusion impaired, hyperintense T2-weighted fluid-attenuated inversion-recovery (FLAIR) lesions, mainly in the left hemisphere. There was no gadolinium enhancement arguing against a cerebral manifestation of the original lymphoma occurring rarely in patients with nMZL. After rapid clinical progression reflected by an increase of leukoencephalopathy in the subsequent brain MRI 4 days later, the diagnosis of PML was confirmed by the detection of JC virus DNA in the CSF (40 copies/mL, high sensitivity PCR; Unilabs A/S, Copenhagen, Denmark). Apart from signs of increased blood-brain barrier permeability, CSF analysis remained normal. CT scans and a bone marrow biopsy showed no signs of recurrent or novel B cell lymphoma.
Four weeks after onset, we initiated treatment with pembrolizumab (2 mg/kg body weight) with a dosage interval of 4 to 6 weeks.1 Three weeks after the initial dose (week 7), the patient was readmitted to hospital because of progressive hemiparalysis with a plegic right arm, cognitive deficits, and nonfluent aphasia. We intensified treatment with pembrolizumab by reducing the interval to 2 weeks, in accordance with another pembrolizumab protocol of a PML case.6 After 5 treatment courses (week 14), the patient achieved a stable clinical condition, but JC viral load in CSF increased to 10,000 copies/mL and further progression of leukoencephalopathy was evident by MRI. At week 23, cranial MRI showed no further progression, but brain atrophy was observed in affected areas. Viral load in CSF was still high (2,262 copies/mL). To enhance virus elimination, we initiated a 5/10 partially human leukocyte antigen (HLA)-matched allogenic BK virus-specific T cell transfusion.4 T cells from a HLA-matched healthy donor from alloCELL registry (20,000 CD3+ cells/kg bodyweight) were administered twice 7 weeks apart (week 24, 31), followed by 5 infusions of pembrolizumab (Figure). Both treatments were tolerated very well. In particular, we did not observe any signs of graft vs host disease. Viral load in CSF dropped to 495 copies/mL (week 46). Brain MRI revealed a slight reduction of FLAIR lesions with a progressive atrophy of affected regions in the left hemisphere and no more diffusion restriction. The patient's clinical condition, particularly aphasia and cognitive deficits, further improved after administration of the virus-specific T cells. However, the right arm remained plegic.
Clinical and MRI stability in particular concerning FLAIR lesions were achieved after the fourth and fifth infusion of pembrolizumab, respectively (11 and 14 weeks after onset). The initial prominent marginal diffusion impairment as a sign of viral activity was no longer detectable 32 weeks after onset. The peak of JC virus load in the cerebral fluid was 10,000 copies/mL 15 weeks after onset. FLAIR = T2-weighted fluid-attenuated inversion-recovery (scoring: hyperintensity); Gd+ = gadolinium enhancement; DWI = diffusion-weighted imaging (scoring: hyperintensity); MRI scoring = - nonexistent, + mild, ++ moderate, +++ profound, and ++++ severe; NIHSS = NIH Stroke Scale.
Discussion
We report a combination of BK virus-specific T cells and pembrolizumab as a treatment option for patients with PML. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. This case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. We did not observe any signs of immune reconstitution inflammatory syndrome. The treatment resulted in clinical improvement and regression of leukoencephalopathy in MRI. Case-control series (and ideally controlled clinical trials) might shed more light on the potential benefit of a sequential or combined treatment with checkpoint inhibitors and allogeneic antigen-specific T cell transfer in PML.
Study Funding
The authors report no targeted funding.
Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.
Appendix Authors

Footnotes
The Article Processing Charge was funded by TUM Open Access Publishing Fund.
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
- Received May 10, 2021.
- Accepted in final form June 10, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
References
- 1.↵
- Cortese I,
- Muranski P,
- Enose-Akahata Y, et al
- 2.↵
- Jubel JM,
- Barbati ZR,
- Burger C,
- Wirtz DC,
- Schildberg FA
- 3.↵
- Pawlitzki M,
- Schneider-Hohendorf T,
- Rolfes L, et al
- 4.↵
- Muftuoglu M,
- Olson A,
- Marin D, et al
- 5.↵
- Gagnier JJ,
- Kienle G,
- Altman DG,
- Moher D,
- Sox H,
- Riley D
- 6.↵
- Rauer S,
- Marks R,
- Urbach H, et al
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Daniel Friedman and Dr. Sharon Chiang
► Watch
Related Articles
- No related articles found.