Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy

Targeting cancer stem cell pathways for cancer therapy

“…In addition to the antibodies against the CSC molecules mentioned above, some novel anti-CSC immunotherapeutic approaches, such as immunologic checkpoint blocking or CAR-T cell therapies, have been developed. Some drugs that target the immune checkpoint receptors CTLA-4, 635 PD-1 (nivolumab, 636 pembrolizumab, 637 and cemiplimab, 638 ) and PD-L1 (avelumab, 639 durvalumab, 640 and atezolizumab 641 ) have also been in clinical trials. I ipilimumab, a CTLA-4 antibody, is approved by the FDA, and initial clinical results showed good effectiveness in patients with metastatic melanoma.…”

Progressive multifocal leukoencephalopathy and anti‐CD20 monoclonal antibodies: What do we know after 20 years of rituximab

“…No definite treatment for PML exists yet, and the rarity of the disease leads most cases to be enrolled in N‐of‐1 clinical trials, which can be classified as follows: direct treatments: 5‐HT 2a antagonists (risperidone, and mirtazapine), mefloquine, cidofovir; qualitative immune reconstitution: vaccination against JCV‐VP1: in contrast to immunocompetent AID patients, vaccination is unlikely to be effective in immunocompromised patients, it is hard to massively deploy in newly diagnosed patients before rituximab initiation; checkpoint inhibitors: after preclinical evidence showed that in PML patients JCV‐specific CD8 + cytotoxic T lymphocytes express PD‐1 more frequently than total CD8 T lymphocytes and that blocking the PD‐1 receptor increases JCV‐specific T‐cell immune response in a subgroup of PML patients, four independent research groups recently reported successful treatment of seven out of 11 PML cases with pembrolizumab and nivolumab, with preexistence of JCV‐specific T cells as a prerequisite for therapeutic success . Nevertheless, some of those patients had concurrent therapies, and five cases of PML have instead been reported after nivolumab; quantitative immune reconstitution: nonspecific: recombinant human IL‐7and IL‐2: T‐cell reconstitution, including reconstitution of normal CD4 + counts, is physiologically‐driven by IL‐7.…”

A case of immune reconstitution syndrome complicating progressive multifocal leukoencephalopathy after kidney transplant: Clinical, pathological, and radiographic features

“…For instance, interleukin‐7 in combination with a JC virus capsid vaccine resulted in CSF JC viral load clearance, MRI improvement, and clinical stabilization of two patients with primary or acquired CD4 lymphopenia, though neither of these agents are readily available, and their benefit remains speculative . One potential drug target is programmed cell death protein 1 (PD‐1), which is a negative regulator of the immune response that is upregulated on CD4+ and CD8+ cells in patients with PML, and which may contribute to impaired JC viral clearance . In a recent study of eight patients with PML (four with hematological malignancies, two with HIV, and two with idiopathic lymphopenia) treated with the PD‐1 inhibitor pembrolizumab, five patients had varying degrees of clinical, virological, and radiographic improvement or stabilization, which correlated with the emergence of a strong anti‐JC virus cell‐mediated immune responses .…”

“…One potential drug target is programmed cell death protein 1 (PD‐1), which is a negative regulator of the immune response that is upregulated on CD4+ and CD8+ cells in patients with PML, and which may contribute to impaired JC viral clearance . In a recent study of eight patients with PML (four with hematological malignancies, two with HIV, and two with idiopathic lymphopenia) treated with the PD‐1 inhibitor pembrolizumab, five patients had varying degrees of clinical, virological, and radiographic improvement or stabilization, which correlated with the emergence of a strong anti‐JC virus cell‐mediated immune responses . One patient had already improved prior to receiving pembrolizumab, and two (one with idiopathic lymphopenia and one with non‐Hodgkin's lymphoma) deteriorated despite receiving it.…”