Dr Irene CorteseIrene Cortese, MD
Results of a study of pembrolizumab for patients with progressive multifocal leukoencephalopathy (PML) have suggested that the IgG4 isotype antibody reduces JC viral load as well increases CD4+ and CD8+ activity against the virus in some patients.1

The trial evaluated a 2-mg/kg dose, administered in 4- to 6-week intervals, in 8 adults with PML, and ultimately revealed a decrease in the detection of programmed cell death protein 1 (PD-1) on lymphocytes in both cerebrospinal fluid (CSF) and peripheral blood. The decrease ranged from 33% to 87% on CD4+ cells, and 38% to 90% on CD8+ cells after the first dose.

“These observations suggested that the PD-1–PD-L1 pathway might play a role in the pathogenesis of PML,” lead author Irene Cortese, MD, clinical director, Neuroimmunology Clinic, National Institute of Neurological Disorders and Stroke (NINDS), and colleagues wrote. Although, they noted that no patient had a complete disappearance of lesions.

“In the months before the first infusion, seven of the eight patients had presented with progressive neurologic deterioration, and MRI showed enlargement of PML lesions,” the investigators explained. “After treatment with pembrolizumab, 5 of the 8 patients had clinical improvement or stabilization, and MRI showed corresponding stabilization or reduction in lesion burden.”

The remaining 5 patients who stabilized had a JC viral load reduction which was temporarily associated with the reinvigoration of in vitro anti–JC virus cellular immune responses. Additionally, 4 of these patients showed a persistent JC viral load reduction as well as a lack of recurring PML ranging from 16 to 26 months after infusion.

The other 3 patients of the full 8-patient cohort showed no clinical benefit derived from pembrolizumab. One had already had clinical, radiologic, and virologic stabilization prior to treatment and remained so. The other 2 patients continued to decline and subsequently died from PML. Pembrolizumab did not induce immune reconstitution inflammatory syndrome (IRIS), save for potentially a single patient.

Additionally, Cortese and colleagues noted that 1 patient had a recurrence of psoriatic rash, and 1 patient had a recurrence of a nonspecific rash.

In an accompanying editorial by Igor J. Koralnik, MD, he questioned if pembrolizumab and nivolumab—referenced from another study in PML—suitable for treatment of PML, noting that “the current reports are encouraging but suggest that the presence of JC virus-specific T cells in the blood is a prerequisite for their use.”2

“A controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML,” Koralnik, the Jean Schweppe Armour Professor of Neurology and Chairperson, Department of Neurological Sciences, Rush Medical College, wrote. Cortese and colleagues acknowledged the limitation of the trial’s size, noting that bigger systematic studies and clinical trials are needed.
 
Koralnik also noted in his editorial that the magnetic resonance imaging (MRI) findings “deserve consideration,” due to the decrease in the size of lesions suggesting treatment efficacy. He noted that these lesions were replaced by atrophy in some instances, a finding in conjunction with the destruction of white matter by PML. “Furthermore, the absence of contrast enhancement on MRI suggests that the immune checkpoint blockers may not have been potent enough to trigger the IRIS,” he explained.

Cortese and coauthors noted that altogether pembrolizumab did not display an evident effect on the hematologic or immune disorders which underlie PML, nor were the improvements the likely explanation for the decrease in JC viral load. But they agreed that patients with neoplastic and lymphopenic disorders cannot be excluded in this possibility.

“Further study of immune checkpoint inhibitors in the treatment of PML is warranted,” they concluded.
REFERENCES
1. Cortese I, Muranski P, Enose-Akhata Y, et al. Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Engl J Med. Published online April 10, 2019. doi: 10.1056/NEJMoa1815039.
2. Koralnik IJ. Can immune checkpoint inhibitors keep JC virus in check? N Engl J Med. Published April 10, 2019. doi: 10.1056/NEJMe1904140.