Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy

Abstract

Objective: Progressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)-specific T cell therapy in a cohort of hematological patients with PML.

Methods: Between 2014 and 2019, 9 patients with a diagnosis of "definite PML" according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV-specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides.

Results: None of the patients experienced treatment-related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV-specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow-up.

Interpretation: Among other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769-779.

FIGURE 1

Magnetic resonance imaging findings at the time of progressive multifocal leukoencephalopathy (PML) diagnosis in Patient 1, in A–E. and Patient 4, in F–L. (A) Patient 1 had a single progressive multifocal leukoencephalopathy (PML) lesion located in the left rolandic white matter, hyperintense on axial FLAIR images. (B) The adjacent cortex shows a characteristic rim of hypointensity on gradient echo (GE) images. (C, D) No diffusion restriction is evident on b1000 sequences, in C, and ADC sequences, in D, and (E) no contrast enhancement was evident on T1 sequences after gadolinium injection. (F) Patient 4 had a large PML lesion in the right parietal white matter that involved the corpus callosum splenium and reached the contralateral hemisphere, evident as hyperintense on FLAIR images. (G) No cortical rim of hypointensity was evident on GE images. (H, I) Linear rims of diffusion restriction were present along the lateral margins of the PML lesion, corresponding to the front of active demyelination. (J) The PML lesion showed marked hypointensity on T1 sequences after gadolinium injection, but no contrast enhancement. FLAIR, Fluid Attenuated Inversion Recovery.

FIGURE 2

Magnetic resonance imaging (MRI) findings in Patient 1. (A–C) Before starting T cell therapy. (D–F) 1 month after T cell therapy discontinuation. (G–I) 2.5 years after T cell therapy discontinuation. (A, D, G) Axial FLAIR images. (B, E, H) T1‐weighted images after gadolinium injection. (C, F, I) Gradient echo (GE) images. (A, B) MRI at initiation of T cell therapy showed a large frontoparietal progressive multifocal leukoencephalopathy (PML) lesion that was hyperintense on FLAIR sequences, shown in A, and hypointense on T1 sequences, with no contrast enhancement after gadolinium injection, shown in B. (D) MRI acquired 1 month after the last T cell therapy infusion showed an initial reduction in the size of the PML lesion on FLAIR images, together with a sharp reduction of its mass effect. (E) On T1 sequences after gadolinium injection, small punctate areas of contrast enhancement had appeared within (or close to) the PML lesion. (G, H) MRI acquired at the last follow‐up showed further reduction of the FLAIR hypersignal, in G, and a major cortical–subcortical atrophy across the left frontoparietal lobes, in G and H. FLAIR, Fluid Attenuated Inversion Recovery.