Use of Pembrolizumab for Treatment of Progressive Multifocal Leukoencephalopathy in People Living with HIV

Abstract

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease occurring in advanced HIV infection, caused by the reactivation of poliomavirus JC (JCV). The use of pembrolizumab for treatment is based on the inhibition of programmed cell death protein 1 (PD-1), potentially improving the anti JCV-specific response. We used pembrolizumab with combined antiretroviral treatment (cART) on a compassionate-use basis. At each administration, clinical evaluation, MRI and laboratory testing, including CD3, CD4, CD8, PD-1 markers, HIV-RNA and JCV-DNA in cerebrospinal fluid (CSF)/plasma pairs, were performed. The JCV-specific T cell response was analysed by Elispot assay. This study included five HIV patients: four male, median age 43 years (29–52), median CD4 and CD8 count 150 (15–158) and 973 (354–1250) cell/mm3, respectively; median JCV-DNA and HIV-RNA in CSF/plasma pairs 9.540/1.503 cps/mL and 2.230/619 cp/mL, respectively. Overall, patients received between two and seven doses of pembrolizumab. After treatment, we observed JCV-DNA reduction and PD-1 down-regulation both in CSF and in plasma (high in circulating CD4 and CD8 at baseline), which remained stable at low levels in all patients. Three out of five patients showed stability of clinical picture and neuroimaging, while two others died. More data are needed in order to identify predictors of response to therapy.

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

“… 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.…”

“… 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.…”

HIV and Co-Infections: Updates and Insights

“…This was more pronounced in those at risk of immune activation. Pinetti, on a pembrolizumab compassionate-use basis, describes the experience of the Italian National Institute of Infectious Diseases in the treatment of progressive multifocal leukoencephalopathy (PML) in people living with HIV [ 2 ]. PML is a severe demyelinating disease caused by the reactivation of poliomavirus JC (JCV), which mainly occurs in immunosuppressive conditions such as those cause by AIDS.…”