Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes

Abstract

Background: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods:To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results:Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion:We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.

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

“…This study reports a series of 9 HIV‐negative patients who developed PML in the context of hematological malignancies or congenital immune deficiencies and who were treated with infusions of JCPyV‐specific T lymphocytes. None of the patients experienced treatment‐related adverse events, strengthening the evidence that T cell therapy is a safe and feasible treatment strategy in this fragile population 25–27 …”

“…Cell lines were generated ad hoc for 7 patients, from autologous or allogenic PBMCs, whereas in 2 cases third‐party banked JCPyV‐specific T cells were used. Whenever possible, the use of an HSCT donor or an HLA‐haploidentical third‐party family donor is preferred in patients with a severe impairment of cellular immunity 27 . However, the significant amount of time required to find an HLA‐compatible family donor, including HLA typing and donor work‐up for leukapheresis, and the lack of availability of suitably matched third‐party T cells prompted us to explore the possibility of expanding JCPyV‐specific T cells from the patient, after performing a small‐scale in vitro virus‐specific immunity test.…”

“…This approach has been used for more than 2 decades in the treatment of refractory herpesvirus infections, 23,24 but has only recently been used in patients with PML. Since the first case was reported by our group in 2011, 25 only 4 additional patients have been treated with T cell therapy 26,27 . Here, we describe the clinical and paraclinical features in a series of 9 HIV‐negative patients treated with T cell therapy at our Institution, with the aim of reporting preliminary data on the efficacy and safety of this approach in view of launching a clinical trial in a larger cohort.…”

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][4][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.…”

“…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.…”