Advances in Treatment of Progressive Multifocal Leukoencephalopathy

Abstract

Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved, PML has a grim prognosis. Innovative strategies have shown promise in promoting anti-JCV immune responses, and include T-cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML. ANN NEUROL 2021;90:865-873.

FIGURE 1

Mode of action of progressive multifocal encephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS) treatments. Left panel: In a patient with immunocompromised condition, JC virus (JCV)‐specific T‐cell pool is reduced and their level of exhaustion (characterized by Programmed cell Death protein 1 [PD‐1] upregulation) is increased (1). Immune checkpoint inhibitors (ICIs) or recombinant human interleukin 7 (rh‐IL‐7) are used to foster JCV‐specific T‐cell proliferation and effector function (2). Alternatively, JCV‐specific T cells may be purified from human leukocyte antigen–matched healthy donors (3) and expanded in vitro with JCV or BK virus (BKV) peptides before adoptive transfer (4). This increase of competent JCV‐specific T‐cell pool allows a reconstitution of the immune surveillance of the central nervous system (CNS; 5). Right panel: In natalizumab‐associated PML, the blockade of α4 integrin expressed by T cells prevents those cells from entering the CNS, as they are unable to bind vascular cell adhesion molecule 1 (VCAM‐1) at the surface of the blood–brain barrier (1). Upon natalizumab withdrawal (including prompt removal through plasma exchange), abrupt restoration of anti‐JCV immunity occurs. This massive infiltration by JCV‐specific T cells triggers an unregulated and potentially harmful immune response within CNS parenchyma, called IRIS (2). This infiltration is dominated by CD8⁺ T cells harboring the CCR5 tissue homing marker (represented by a red receptor at cell surface). Thus, CCR5 agonist may theoretically be used to prevent massive influx of T cells and IRIS (3). Alternatively, granulocyte‐colony–stimulating factor (G‐CSF) has been proposed to induce immune reconstitution and CNS migration through pathways independent of α4/VCAM‐1 interaction (4). [Color figure can be viewed at www.annalsofneurology.org]