Combined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy

Abstract

ObjectiveWe report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML).ResultsA 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.DiscussionThis 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.

Combined treatment with allogeneic Epstein–Barr- and human polyomavirus 1 specific T-cells in progressive multifocal leukoencephalopathy and EBV infection: a case report

“…Furthermore, as indicated by previous studies, ICI may not be optimal in cases lacking endogenous virus-specific T-cells. 5 , 6 , 25 Considering this, we believe that our choice of DIAVIS T-cell infusion over ICI therapy in this case, guided by an extensive pre-treatment evaluation of the patient’s immune status, played a critical role in the successful outcome.…”

“… 39 Although there are no approved medications, experimental treatments involving ICIs and the application of virus specific allogenic T-cells have been utilized in treatment. 7 – 14 , 20 – 26 , 28 , 29 , 39 However, out of 91 PML patients treated with ICI, only 12 were related to AIDS. 20 Within this subgroup, 6 out of 12 patients died within a year, with causes including PML progression, PML-induced IRIS, and a combination of PML with other contributing diseases.…”

“…The production process is detailed in prior publications. 23 , 25 Prior to manufacturing, the frequencies of BKV and EBV specific T cells were determined to identify a suitable T-cell donor. This was done using the IFN-γ Cytokine Secretion Assay, which is largely analogous to clinical-grade manufacturing.…”

“… 4 Until recently, there were no effective treatment options for this often-fatal disease. Within the last years, the use of anti-PD-1 (programmed cell death protein 1) antibodies (immune checkpoint inhibitor, ICI), 5 – 20 and the application of allogeneic virus-specific T-cells 21 – 29 have shown encouraging treatment results for some PML patients. Notably, the absence of virus-specific T-lymphocytes in the blood has been identified as a negative prognostic factor in HIV-positive PML-patients.…”

JC virus-induced progressive multifocal leukoencephalopathy in a presumably healthy patient

“…However, there is no in vivo experiment to prove its efficacy, as there is no suitable animal model for PML. Pembrolizumab, a PD-1 blocker, was reported effective in some PML cases with previous lymphoma or other immune related diseases [7,8]. Whether pembrolizumab is also effective in immunocompetent patients need more clinical studies [9].…”