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

Allogeneic BK Virus-Specific T-Cell Treatment in 2 Patients With Progressive Multifocal Leukoencephalopathy

“…Our observations support the conclusions drawn from a previous series of patients treated with allogeneic BKV-CTLs. 3 - 5 Although the therapeutic responses in these studies are consistent, there were major differences in the protocols to prepare the donor cells. The preceding case series applied preproduced frozen cell lines from autologous or allogeneic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides.…”

“…The preceding case series applied preproduced frozen cell lines from autologous or allogeneic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides. 3 - 5 By contrast, we have accessed a preexamined registry of >2,000 potential donors and identified the most suitable donors based on HLA typing and T-cell frequencies. Direct isolation of antigen-specific T cells by stimulation with peptide pools followed by cytokine capture and magnetic isolation provides a rapid method to produce antiviral T cells under good manufacturing production guidelines within 16–24 hours.…”

“…A few case series of patients with PML transplanted with allogeneic BK virus-specific T cells (BKV-CTL) demonstrated alleviation of symptoms, demyelinating lesions, and JC virus load. 3 - 5 In this study, we treated 2 patients with PML successfully with allogeneic BKV-CTL using different protocols for the donor cell preparation and different T-cell monitoring approaches.…”

Innovative therapeutic concepts of progressive multifocal leukoencephalopathy

“…In January 2021, an Italian group published a case series on HPyV-2-specific T-cell therapy in nine PML patients, in which cell lines were derived from autologous or allogeneic peripheral blood mononuclear cells by stimulation with protein multimers in a procedure of approximately 4 weeks [86]. Seven of the nine patients suffered from malignant hematologic diseases, six of whom had previously received B-cell depleting therapy (rituximab).…”

“…In five cases, the HPyV-2-specific cellular immune response was analyzed before and after cell therapy. In four of five patients, there was a relevant increase in interferon-gamma (IFN)-producing HPyV-2-specific T cells after T-cell application, which in turn correlated with a favorable outcome [86].…”