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Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy

The Guru et al study (Saudi J Kidney Dis Transpl 2019;30(2):526-30) describes a case of progressive multifocal leukoencephalopathy (PML) occurring in a renal transplant patient who subsequently expired. They have listed the limited options available for treatment but note a uniformly fatal outcome with a median survival of 6.4 months. Cortese et al article published in the New England Journal of Medicine reported a significant advance in treatment of this disease, with the use of immune checkpoint inhibitors (CPi) – pembrolizumab and nivolumab. These drugs are Food and Drug Administration approved for immunotherapy of multiple cancers. The interaction between Programmed cell death protein 1 (PD1) (on the cytotoxic T-cells) and programmed death ligand 1 (PD-L1) (on the tumor cells) induce immune tolerance for the cancer cells; CPi block this interaction and invigorate the antitumor activity of T-cells. Three groups reported the use of these drugs in treatment of PML arising in 10 patients of hematological disorders or HIV infection. Seven of them improved to varying degrees, and as the editorial notes, the presence of JC virusspecific T-cells in the blood appears to be a prerequisite for their use, something not reported in this case. Other success stories have appeared in recent literature. These series however did not include any organ transplant patients, and it would be interesting to see whether CPi work in this group without significant adverse events. CPi are relatively contraindicated in patients on steroids [such as those with autoimmune disorders and organ transplant, as steroids may (theoretically) prevent the immune stimulation] but have been used in transplant patients for treatment of malignancies, with both tumor regression and graft rejection. Hence, the risk to benefit ratio must be carefully considered before using CPi for PML in transplant patients. Interestingly, CPi themselves are associated with PML.