Long-term outcome of progressive multifocal leukoencephalopathy with recombinant interleukin-2 treatment and an associated increase in the number of HPyV-2-specific T-cells: a case report

Abstract

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by reactivation of the human polyomavirus 2 (HPyV-2). PML is associated with a high morbidity and mortality rate and there is currently no standard curative therapy. We report short-term immunologic response and long-term clinical outcomes in a patient diagnosed with follicular lymphoma (FL) who developed PML. Diagnosis of PML was established conclusively based on findings from a brain biopsy. The patient was treated with recombinant interleukin 2 (IL-2) and showed rapid clinical improvement. HPyV-2-specific T-cells were tracked longitudinally and correlation with clinical status, viral load, and radiographic imaging was documented. After the progression of the patient’s FL, which required an allogeneic bone marrow transplant, the patient prophylactically received human leukocyte antigen-matched donor-derived HPyV-2 T-cells to prevent the recurrence of the PML as part of a clinical trial. Twelve years after the initial diagnosis of PML, he did not develop a relapse of his PML, supporting data that therapies that increase HPyV-2-specific T-cells, including IL-2, may be effective in the management of PML.

Keywords

case report follicular lymphoma IL-2 non-Hodgkin lymphoma progressive multifocal leukoencephalopathy

Introduction

Progressive multifocal leukoencephalopathy (PML) is a rare relentlessly demyelinating disease caused by the reactivation of the human polyomavirus 2 (HPyV-2) (formerly known as the JC virus). HPyV-2 is a small non-enveloped polyomavirus with a circular double-stranded DNA genome that contains three main regions. The early region encodes for large T and small T antigens which are required for viral transformation, gene regulation, and replication, and are transcribed prior to DNA replication. Late genes are transcribed after gene transcription and encode for the agnoprotein and viral capsid proteins VP1, VP2, and VP3. The noncoding control regions contain transcription factor binding sites that regulate the expression of both early and late genes.^1,2

Infection of the mucosal surfaces with HPyV-2 often happens asymptomatically and is common during childhood. Viremic spread occurs to other tissues and organs, and the infection is thought to persist quiescently in the host cell. In patients with compromised cellular immunity, however, HPyV-2 can undergo complex sequential DNA sequence alteration of the noncoding control region as well as in VP1, which may help explain the ability to, in rare cases, infect the oligodendrocytes of the central nervous system (CNS).^3,4 Oligodendrocytes are the myelin-producing cells of the CNS, and destruction of the oligodendrocytes leads to demyelination that occurs in a multifocal distribution causing PML.^2,5,6

PML is most commonly seen in patients with HIV/AIDS,⁷ as well as in patients with multiple sclerosis and Crohn’s disease who are treated with natalizumab, a monoclonal antibody against the alpha-4 subunit of integrin molecules on T cells, restricting trafficking of T cells to the CNS. Previously, PML was also seen in patients with psoriasis treated with efalizumab, an immunomodulatory monoclonal antibody against CD11a present in T cells.⁸ This drug was withdrawn from the market due to PML side effects.

PML is associated with a high morbidity and mortality rate.⁹ Neurological deficits are associated with the areas of demyelination of the brain. There is currently no standard therapy. The most effective strategy to treat PML is to reconstitute the immune response, and its success largely depends on early diagnosis and rapid and effective immune repletion. Symptoms significantly improved after treatment of HIV/AIDS patients with anti-retroviral therapy. In patients undergoing solid organ or bone marrow transplant, or with an auto-immune disorder, PML improved after reduction of immunosuppression.^10
–13 In patients where the compromised immune system cannot simply be reversed by discontinuation of immunosuppressive agents (e.g. in patients with a primary immunodeficiency or lymphoproliferative and myeloproliferative disorders), it has been reported that the immune response against the HPyV-2 can be improved by increasing the number and activity of HPyV-2-specific T-cells. This increase can be accomplished by either directly stimulating T cells with growth factors [e.g. interleukin (IL)-2, IL-7], or by adoptively transferring HPyV-2-specific T-cells.^14
–17 In addition, treatment with immune checkpoint inhibitors to facilitate the immune response has been investigated. While results were encouraging, checkpoint inhibition did not convincingly prolong survival or reduce neurological disability overall.^18,19

In this report, we describe a patient diagnosed with advanced stage follicular lymphoma (FL) who developed PML in the setting of prior chemo-immunotherapy. Rapid and sustained improvement of his PML occurred after administration of recombinant IL-2, which was associated with a marked increase in HPyV-2-specific T-cells. During the course of his treatment, his FL progressed, requiring an allogeneic hematopoietic stem cell transplant (HSCT) from an unrelated donor. To prevent a flare-up of his prior PML, he prophylactically received donor-derived human leukocyte antigen (HLA)-matched T-cells with anti-HPyV-2 activity after his HSCT as part of a phase I clinical trial.²⁰ He remained well 12 years after the initial diagnosis of PML, suggesting that therapies that increase HPyV-2-specific T-cells may be effective in the management of PML.

Methods

Portions of cerebrospinal fluid and peripheral blood specimens were sent to the NIH for viral load calculations using quantitative PCR analysis and T-cell population analyses.²¹ As published previously, peripheral blood mononucleated cells were isolated and stimulated with five pools of peptides covering the HPyV-2 proteome: large T antigen, small T antigen, VP1, VP2, and agnoprotein.²² For measurement of cytomegalovirus (CMV)-specific T-cells, CMV pp65 peptides obtained from JPT Peptide Technology were used. Responses were measured by intracellular cytokine staining and polychromatic flow cytometry for cytokines associated with effective control of viral infections: interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Given that expansion of memory T cells in the setting of PML occurs before naïve T cells²³ and that low frequencies of central memory T cells are associated with a risk of PML,²⁴ memory T-cell responses were measured. The reporting of this study conforms to the CARE case report guidelines.²⁵

Case

A 48-year-old male with no past medical history was diagnosed in May 2007 with FL Grade 2, Ann Arbor stage IV. The diagnosis was confirmed histologically on tissue obtained from a lymph node in the left inguinal area. He was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for six cycles and attained complete remission. Subsequently, he received maintenance therapy with rituximab administered every 3 months for the first two cycles followed by every 6 months for the next cycles, until June 2009 when he relapsed. Because of the low-burden disease, he proceeded with watchful waiting. His disease further progressed in March 2010 and he was enrolled in an autologous recombinant idiotypic vaccine phase I clinical trial for the treatment of patients with relapsed or transformed FL (NCT01022255).²⁶ He received three cycles of bendamustine resulting in a good clinical response. A fourth cycle of the bendamustine was deferred due to low blood counts. Twelve weeks after completion of the last dose of bendamustine, he received two subcutaneous injections of 1 mg anti-idiotype vaccine (Icon Genetics GmbH, Halle (Saale), Germany) each 4 weeks apart along with subcutaneous 125 µg granulocyte-macrophage colony-stimulating factor following the vaccination administration on Days 1–4.

Two weeks after administration of the idiotypic vaccine, however, he developed marked weakness and a pronator drift of his left upper extremity and confusion. A magnetic resonance imaging (MRI) of the brain was performed, showing a lesion in the posterior right frontal lobe with mass effect and patchy enhancement [Figure 1(a)]. While awaiting the final diagnosis and to reduce the inflammation, he was empirically treated with dexamethasone 4 mg twice daily for a total of 10 days. Stereotactic needle biopsy of the brain lesion demonstrated inflammatory infiltrates composed of CD68⁺ macrophages, reactive astrocytes, and CD3⁺ small lymphocytes, as well as several, enlarged, highly hyperchromatic nuclei positive for HPyV-2 by in situ hybridization consistent with a diagnosis of PML (Figure 2). Participation in the idiotype vaccine trial was discontinued.

Figure 1.

(a) Imaging showing the initial axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) of the patient’s brain, showing a hyper-intensive lesion in the posterior right frontal lobe. Typical for PML is sparing of the more superficial cortex. (b–d) Images obtained at days 12, 40, and 720 post-treatment initiation, showed significant resolution based on a decrease in the hyperintensity of the lesion.

Figure 2.

Histopathology of brain biopsy. (a) H&E stain showing enlarged astrocytes with a large inclusion-bearing nucleus, (b) chromogenic in situ hybridization (CISH) for the JC virus.

To increase HPyV-2-specific T-cells to treat the PML, he was then treated with recombinant IL-2; 500,000 units of IL-2 subcutaneously on Day 1 followed by 1,000,000 units daily thereafter. Dexamethasone 4 mg twice daily was continued for an additional 7 days as prophylaxis for immune reconstitution inflammatory syndrome. He reported subjective clinical improvement within a few days, and after 1 week his physical examination was significantly improved in left upper extremity strength. An MRI performed on Day 12 showed evident resolution of previous radiographic abnormalities [Figure 1(b)–(d)]. He continued to improve clinically and radiographically and returned to full daily activities. He remained on IL-2 therapy continuously.

His FL gradually progressed and by May 2012 he had extensive disease requiring further therapy. He received one additional cycle of bendamustine and rituximab, radiotherapy, and two cycles of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). A near-complete response to therapy was achieved and in December 2012, he underwent allogeneic HSCT from an HLA-matched unrelated donor utilizing a reduced intensity preparative regimen with fludarabine and melphalan. IL-2 treatment was discontinued 1 week before the stem cell infusion date. Post-HSCT immunosuppression included treatment with tacrolimus and methotrexate. Given his history of PML and risk of reactivation following HSCT, he received a single prophylactic infusion of HLA-matched donor-derived polyomavirus reactive T cells (5 × 10⁶ cells/m² body surface) on Day +41 post-HSCT as part of the phase I clinical trial (NCT01570283). Virus-specific cytotoxic T-cells were made by direct stimulation of donor-derived peripheral blood mononuclear cells with overlapping peptide libraries that incorporated antigens from the Epstein–Barr virus, CMV, adenovirus, human herpes virus, and BK virus (with cross-recognition of the HPyV-2 homolog sequence).²⁰ More information about the generation of the T-cell-specific cells is published by Papadopoulou et al.²⁰ His allogeneic HSCT was complicated by mild chronic graft-versus-host disease (GVHD) involving the skin and liver that responded to tacrolimus and corticosteroids. Corticosteroids were tapered off and he remained on a small dose of tacrolimus. He did not develop any opportunistic infections. Twelve years after his PML diagnosis, there was no evidence of recurrence of the PML, and his lymphoma remained in remission. A timeline highlighting his disease and treatment history is illustrated in Figure 3.

Figure 3.

Timeline of his diagnostic and treatment history.

Results

During the treatment with recombinant IL-2, there was a clinical and radiographic response (Figure 1) and normalization of his neurologic status. Biochemical analysis of his blood and CSF specimens showed a reduction in viral load [Figure 4(a)] that occurred during the expansion of HPyV-2-specific T-cell populations [Figure 4(b) and (c)]. The absolute number and frequency of CD4⁺ T cells by IFN-γ and TNF-α production were measured after stimulation with peptides covering the HPyV-2 proteome, including the large T antigen and small T antigen, both early regulatory proteins, VP1 and VP2, a major and minor viral capsid protein, and the agnoprotein, which is a late regulatory protein. After the start of treatment with IL-2, an increase was seen in HPyV-2-specific T-cells directed against the large T, VP1, and VP2, as well as in T cells responding to the CMV. No increase was seen in T cells directed against the small T antigen, the agnoprotein, or mitogen staphylococcal enterotoxin B.

Figure 4.

(a) Decrease in a number of HPyV-2 copies in cerebrospinal fluid and serum after the start of interleukin 2 treatment. (b, c) Absolute number and frequency as a proportion to the general T-cell population of CD4⁺ memory T cells by IFN-γ and TNF-α production after stimulation with peptides covering the HPyV-2 proteome: large T antigen, small T antigen (early regulatory proteins), VP1, VP2 (major and minor viral capsid proteins), and agnoprotein (late regulatory protein), as well as a cytomegalovirus antigen and mitogen staphylococcal enterotoxin B (SEB).

Discussion

Primary infection with HPyV-2 is generally asymptomatic and most adults are infected with HPyV-2 in a persistent latent state.²⁷ Although the mechanisms of viral control are not completely delineated, both humoral and cellular mechanisms, in particular virus-specific CD4⁺ and CD8⁺ T-cells, are understood to play a role.²⁸ States of immunosuppression can allow the virus to proliferate and infect oligodendrocytes leading to PML.⁹ Our patient had previously received rituximab and bendamustine, both of which have been associated with PML.^29
–33 The prognosis of PML is very poor but good outcomes have been seen in patients who received treatments aimed at increasing T-cell numbers and function. We had previously observed improved CD4⁺ T-cell numbers and resolution of opportunistic infections in a patient with idiopathic CD4 lymphopenia treated with IL-2,³⁴ and we reasoned that our patient who was immunocompromised from chemotherapy and immunotherapy might benefit from recombinant IL-2 treatment. Our patient had significant clinical and radiographic improvement soon after beginning IL-2 therapy. This clinical improvement was associated with an expansion of HPyV-2 CD4⁺ memory T cells (Figure 4). The patient remains free of PML relapse several years after therapy.

A few additional points are worth addressing with regard to this patient’s particular case. First, the patient developed symptoms fairly soon after receiving an idiotype vaccine, raising the question of whether the vaccine may have caused or unmasked the PML. While this is possible, a mechanistic explanation is unclear and PML was not observed in other patients in this trial (n = 27)²⁶ or in other anti-idiotype vaccine trials. Second, it is worth noting that we administered IL-2 for a prolonged period after the patient’s initial response. This was done because of concern for high risk of PML relapse, in view of the patient’s state of ongoing immunosuppression from his lymphoma and prior immunosuppressive therapy. Whether the prolonged IL-2 may have had any role in the patient’s subsequent lymphoma relapse is speculative; we would note that the patient’s risk of lymphoma relapse was quite high on clinical grounds, in view of his aggressive initial presentation and, in particular, his short disease-free interval after initial therapy. Lastly, this patient received virus-specific T-cells from his allogeneic HSCT donor as part of a clinical trial.²⁰ At the time of his allogeneic HSCT, the patient did not have evidence of PML. However, we were concerned about the possibility of PML relapse in the setting of profound post-allogeneic HSCT-associated immunosuppression. We were reluctant to continue IL-2 in the post-transplant setting because of the possibility of exacerbating GVHD. Therefore, we referred the patient for participation in a clinical trial investigating infusion of allogeneic donor-derived virus-specific T-cells which included T cells with activity against BK virus antigens (which cross-react with HPyV-2 antigens). The patient did not have recurrence of PML but the role of the allogeneic virus-specific T-cells is unknown since the patient had no evidence of disease when the cells were given.

Only a handful of cases have been described showing clinical improvement in PML patients when treated with IL-2.^14,35
–38 Our results add to these previous observations by demonstrating a marked rise in HPyV-2-specific T-cells in association with resolution of HPyV-2 viremia and clinical improvement, which was not measured in the majority of prior reports. Case reports have also described varied clinical improvement after treatment with other T-cell-stimulating ILs, including IL-7,^{15
–17,39
–42} a cytokine regulating peripheral T-cell survival and homeostasis, and the IL-15 super-agonist N-803,⁴³ which is critical for the proliferation and activation of natural killer cells and CD8⁺ memory T cells. A retrospective observational study of 64 patients reported a 1-year overall survival following recombinant IL-7 initiation of only 54%.⁴⁴ Based on the literature, there are no associations described between the development of lymphoma and IL treatment. Given that the patient had demonstrated the development of a clinically aggressive FL with early relapse that occurred prior to the onset of the PML, we believe that the recurrence of his lymphoma was unlikely associated with prolonged IL-2 therapy.

Other approaches that have been studied to improving the immune control of the HPyV-2 aiming to increase in HPyV-2-specific CD4⁺ and CD8⁺ T cells include viral-like particle vaccines,^42,45
–50 immune checkpoint inhibitors, and adoptive transfer of polyclonal T cells. The immune checkpoint inhibitors pembrolizumab and nivolumab have been investigated based on the observation that the expression of programmed cell death protein 1 is elevated in blood and CSF CD4⁺ and CD8⁺ T cells in patients with PML.^{18,19,51
–53} Mixed results have been reported. The largest retrospective study that included 79 PML patients reported a 1-year survival of 51%.⁵⁴

Partially HLA-matched multi-virus-specific polyclonal CD4⁺ and CD8⁺ cells with or without ex vivo expansion have shown promise in treating active infections in patients with post-solid organ transplantation or HSCT or with other immunosuppressed states but have only been described in a small number of cases.^20,55
–58 Papadopoulou et al.²⁰ reported eleven patients of which eight patients had up to four active infections, with a virological and clinical response in 94%. Another study reported three patients with PML treated with virus-specific T-cells with ex vivo expansion of which two showed clinical improvement and the third had stabilization of the disease with a reduction in the HPyV-2 viral load.⁵⁷

In summary, PML that has occurred in the setting of chemotherapy or immunotherapy-associated immunosuppression is considered to have a dismal prognosis. Our observation and others suggest that the disease in this setting might be amenable to treatment with approaches that increase the numbers of HPyV-2-specific T-cells. Further investigation with controlled studies as well as evaluation of immunological correlations is encouraged.

Footnotes

Acknowledgements

We extend our gratitude to the patient of the Harold C. Simmons Comprehensive Cancer Center.

Declarations

ORCID iD

Fieke W. Hoff

References

Frisque

Bream

Cannella

. Human polyomavirus JC virus genome. J Virol 1984; 51: 458–469.

Boothpur

Brennan

. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol 2010; 47: 306–312.

Cortese

Reich

Nath

. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol 2021; 17: 37–51.

Johnson

Wortman

Dagdanova

, et al. Polyomavirus JC in the context of immunosuppression: a series of adaptive, DNA replication-driven recombination events in the development of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013; 2013: 197807.

White

Khalili

. Pathogenesis of progressive multifocal leukoencephalopathy – revisited. J Infect Dis 2011; 203: 578–586.

Zurhein

Chou

. Particles resembling papova viruses in human cerebral demyelinating disease. Science 1965; 3676: 1477–1479.

Elliot

Aromin

Gold

, et al. 2.5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy. Lancet 1997; 349: 850.

Bohra

Sokol

Dalia

. Progressive multifocal leukoencephalopathy and monoclonal antibodies. Cancer Control 2017; 24: 1073274817729901.

Tan

Koralnik

. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010; 9: 425–437.

10.

Dahlhaus

Hoepner

Chan

, et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013; 84: 1068–1074.

11.

Ohara

Kataoka

Nakamichi

, et al. Favorable outcome after withdrawal of immunosuppressant therapy in progressive multifocal leukoencephalopathy after renal transplantation: case report and literature review. J Neurol Sci 2014; 341: 144–146.

12.

Sauer

Gölitz

Jacobi

, et al. Good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient: importance of early detection and rapid immune reconstitution. J Neurol Sci 2017; 375: 76–79.

13.

Crowder

Gyure

Drachenberg

, et al. Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant 2005; 5: 1151–1158.

14.

Kunschner

Scott

. Sustained recovery of progressive multifocal leukoencephalopathy after treatment with IL-2. Neurology 2005; 65: 1510.

15.

Alstadhaug

Croughs

Henriksen

, et al. Treatment of progressive multifocal leukoencephalopathy with interleukin 7. JAMA Neurol 2014; 71: 1030–1035.

16.

Guille

Rousset

Bonneville

, et al. IL-7 immunotherapy for progressive multifocal leukoencephalopathy in a patient with already controlled HIV-1 infection on antiretroviral therapy. AIDS 2019; 33: 1954–1956.

17.

Harel

Horng

Gustafson

, et al. Successful treatment of progressive multifocal leukoencephalopathy with recombinant interleukin-7 and maraviroc in a patient with idiopathic CD4 lymphocytopenia. J Neurovirol 2018; 24: 652–655.

18.

Cortese

Muranski

Enose-Akahata

, et al. Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Eng J Med 2019; 380: 1597–1605.

19.

Treiner

Bonneville

Walter

, et al. Treatment of progressive multifocal leukoencephalopathy with nivolumab. N Eng J Med 2019; 380: 1674–1676.

20.

Papadopoulou

Gerdemann

Katari

, et al. Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Sci Transl Med 2014; 6: 242ra83.

21.

Ryschkewitsch

Jensen

Hou

, et al. Comparison of PCR-southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods 2004; 121: 217–221.

22.

Perkins

Ryschkewitsch

Liebner

, et al. Changes in JC virus-specific T cell responses during natalizumab treatment and in natalizumab-associated progressive multifocal leukoencephalopathy. PLoS Pathog 2012; 8: e1003014.

23.

Berard

Tough

. Qualitative differences between naïve and memory T cells. Immunology 2002; 106: 127–138.

24.

Dubois

Ruschil

Bischof

. Low frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy. Neurol Neuroimmunol Neuroinflamm 2015; 2: e177.

25.

Gagnier

Kienle

Altman

, et al. The CARE guidelines: consensus-based clinical case reporting guideline development. J Med Case Rep 2013; 7(1): 223.

26.

Tusé

Bendandi

, et al. Clinical safety and immunogenicity of tumor-targeted, plant-made Id-KLH conjugate vaccines for follicular lymphoma. BioMed Res Int 2015; 2015: 648143.

27.

Weber

Trebst

Frye

, et al. Analysis of the systemic and intrathecal humoral immune response in progressive multifocal leukoencephalopathy. J Infect Dis 1997; 176: 250–254.

28.

Beltrami

Gordon

. Immune surveillance and response to JC virus infection and PML. J Neurovirol 2014; 20: 137–149.

29.

Carson

Evens

Richey

, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009; 113: 4834–4840.

30.

Warsch

Hosein

Morris

, et al. Progressive multifocal leukoencephalopathy following treatment with bendamustine and rituximab. Int J Hematol 2012; 96: 274–278.

31.

Focosi

Tuccori

Maggi

. Progressive multifocal leukoencephalopathy and anti-CD20 monoclonal antibodies: what do we know after 20 years of rituximab. Rev Med Virol 2019; 29: e2077.

32.

Klippstein

Schneider

Sayer

, et al. Pneumocystis carinii pneumonia as a complication of bendamustine monotherapy in a patient with advanced progressive breast cancer. J Cancer Res Clin Oncol 2003; 129: 316–319.

33.

Tsimberidou

Younes

Romaguera

, et al. Immunosuppression and infectious complications in patients with stage IV indolent lymphoma treated with a fludarabine, mitoxantrone, and dexamethasone regimen. Cancer 2005; 104: 345–353.

34.

Trojan

Collins

Khan

. Safety and efficacy of treatment using interleukin-2 in a patient with idiopathic CD4+ lymphopenia and Mycobacterium avium-intracellulare. Clin Exp Immunol 2009; 156: 440–445.

35.

Dubey

Zhang

Graves

, et al. Use of interleukin-2 for management of natalizumab-associated progressive multifocal leukoencephalopathy: case report and review of literature. Ther Adv Neurol Disord 2016; 9: 211–215.

36.

Buckanovich

Liu

Stricker

, et al. Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin’s lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy. Ann Hematol 2002; 81: 410–413.

37.

Przepiorka

Jaeckle

Birdwell

, et al. Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2. Bone Marrow Transplant 1997; 20: 983–987.

38.

Bamborschke

Feiden

, et al. Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation and alpha-interferon immunotherapy. Bone Marrow Transplant 1999; 23: 295–298.

39.

Gasnault

de Goër de Herve

Michot

, et al. Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy. Open Forum Infect Dis 2014; 1: ofu074.

40.

Miskin

Chalkias

Dang

, et al. Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia. Neurol Neuroimmunol Neuroinflamm 2016; 3: e213.

41.

Patel

Ikwuagwu

. A case of progressive multifocal leukoencephalopathy and idiopathic CD4⁺ lymphocytopenia. J Antimicrob Chemother 2010; 65: 2697–2698.

42.

Sospedra

Schippling

Croughs

, et al. Treating progressive multifocal leukoencephalopathy with interleukin 7 and vaccination with JC virus capsid protein VP1. Clin Infect Dis 2014; 59: 1588–1592.

43.

Oza

Rettig

Powell

, et al. Interleukin-15 superagonist (N-803) treatment of PML and JCV in a post-allogeneic hematopoietic stem cell transplant patient. Blood Adv 2020; 4: 2387–2391.

44.

Lajaunie

Mainardi

Gasnault

, et al. Outcome of progressive multifocal leukoencephalopathy treated by interleukin-7. Ann Neurol 2022; 91: 496–505.

45.

Weber

Goldmann

Krämer

, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001; 49: 636–642.

46.

Dang

Koralnik

. A granule cell neuron-associated JC virus variant has a unique deletion in the VP1 gene. J Gen Virol 2006; 87: 2533–2537.

47.

Sunyaev

Lugovskoy

Simon

, et al. Adaptive mutations in the JC virus protein capsid are associated with progressive multifocal leukoencephalopathy (PML). PLoS Genet 2009; 5: e1000368.

48.

Gorelik

Reid

Testa

, et al. Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis 2011; 204: 103–114.

49.

Reid

Sur

, et al. Sequencing and analysis of JC virus DNA from natalizumab-treated PML patients. J Infect Dis 2011; 204: 237–244.

50.

Dang

Vidal

Penalva De Oliveira

, et al. JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. J Gen Virol 2012; 93: 175–183.

51.

Audemard-Verger

Gasnault

Faisant

, et al. Sustained response and rationale of programmed cell death-1-targeting for progressive multifocal leukoencephalopathy. Open Forum Infect Dis 2019; 6: ofz374.

52.

Nath

Rauer

Weiller

, et al. Treatment of progressive multifocal leukoencephalopathy with pembrolizumab. N Eng J Med 2019; 380: 1676–1677.

53.

Mahler

Andrews

Henson

, et al. Sequential interleukin 2 and pembrolizumab use in progressive multifocal leukoencephalopathy. Neurol Neuroimmunol Neuroinflamm 2020; 7: e756.

54.

Boumaza

Bonneau

Roos-Weil

, et al. Progressive multifocal leukoencephalopathy treated by immune checkpoint inhibitors. Ann Neurol 2023; 93: 257–270.

55.

Leen

Bollard

Mendizabal

, et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 2013; 121: 5113–5123.

56.

Houghtelin

Bollard

. Virus-specific T cells for the immunocompromised patient. Front Immunol 2017; 8: 1272.

57.

Muftuoglu

Olson

Marin

, et al. Allogeneic BK virus-specific T cells for progressive multifocal leukoencephalopathy. N Eng J Med 2018; 379: 1443–1451.

58.

Rubinstein

Jodele

Heyenbruch

, et al. Off-the-shelf third-party virus-specific T cell therapy to treat jc polyomavirus infection in hematopoietic stem cell transplantation recipients. Transplant Cell Ther 2022; 28: 116.e1–116.e7.