La Terapia Cellulare nella PML

Transcription

1 Update sulle Malattie Infiammatorie e Infettive del SNC Pavia, 25 maggio 218 La Terapia Cellulare nella PML Sabrina Basso Oncoematologia Pediatrica Fondazione IRCCS Policlinico S. Matteo, Pavia Polyomavirus infection and disease Circular double-stranded DNA of 51 bp 2 regulatory proteins, 3 structural proteins early genes non-coding control region late genes Egli et al. 29 J Inf Dis Kean et al. 29 Plos Pathog White et al. 213 Plos Pathog Ehlers et al. 213 APMIS 1

2 Polyomavirus JC: the virus JCPyV exposure is bi-phasic: 25% throughout childhood to reach 6-7% in the 6 th decade 1-2% of seroconversion per year JCPyV route of transmission and latency sites are unresolved JCPyV persists in the renourinary tract; 1/3 of infected immunocompetent individuals exhibit asymptomatic viruria Other possible sites of latency: B lymphocytes, BM stem/stromal cells, tonsils, enteric LN, spleen, CNS Virtually all cases of JCPyV-related disease occur in immunocompromised individuals PML other CNS disorders (neuronopathy, encephalopathy) interstitial nephropathy (PyVAN) malignancy (?) 1. Egli A et al. J Infect Dis 29;199:837 46; 2. Ferenczy MW et al. Clin Microbiol Rev 212;25: Hirsch HH et al. APMIS 213;121: Polyomavirus JC and PML PML is a rare demyelinating disease of CNS caused by JCPyV primary infection in tonsil stroma cells JCPyV-related PML: reactivation of virus in peripheral blood B lymphocytes; B cells carry the virus to CNS: lytic infection of oligodendrocytes Stage of infection Initial Viral dissemination Latency Reactivation Viral dissemination Productive Demyelination, and progressive multifocal leukoencephalopathy 1. Sabath BF, Major EO. J Infect Dis 22;186(s2):18 6; 2. Ferenczy MW et al. Clin Microbiol Rev 212;25:

3 PML: clinical features Cohorts at increased risk: patients with HIV/AIDS patients with autoimmune diseases or cancer treated with monoclonal Ab (anti-α4 β1 integrin, anti-lfa-1, anti-cd2) transplant recipients patients with primary immune deficiency Symptoms: initial symptoms often go unnoticed: change in personality or decreased cognitive ability gradual progression 1.Tan CS, Koralnik IJ. Lancet Neurology 21; 9: Ferenczy MW et al. Clin Microbiol Rev 212;25: Hirsch HH et al. APMIS 213;121: PML: prognosis and treatment PML outcomes varies with severity/location of lesions, underlying condition and ability to mount an immune response to JCPyV HIV/AIDS: with introduction of cart, mortality decreased of about 5% SOT and HSCT recipients: 1-y survival 56%, overall case fatality >8% In survivors significant neurological impairment may persist No specific antiviral treatment: anedoctal cases treated with nucleoside analogues, or serotonin reuptake blockers enhancement of virus-specific immunity: cart in HIV/AIDS reduction of IS in transplant recipients MoAb therapies discontinuation in MS/other autoimmune disorders or cancer 1.Tan CS, Koralnik IJ. Lancet Neurology 21; 9: Ferenczy MW et al. Clin Microbiol Rev 212;25: Hirsch HH et al. APMIS 213;121:

4 PML: immune response to JCPyV Appearance of JCV-specific cellular immunity, both in peripheral blood and in CSF samples, is associated with improved outcome in AIDS patients CD8+ CTLs play a major role in controlling PML there is evidence that also CD4+ T cells contribute to the response 1. Koralnik IJ et al. J Virol 21; 75: Khanna N et al. J Virol 29;83: Gheuens et al. J Virol 211; 85:7256 Polyomavirus disease and immune reconstitution JCPyV replication and PML seem to be consequences of impaired specific immune function: monitoring of JCPyV-specific T cell immunity restoration of specific immunity in high-risk patients through cellular immunotherapy may represent valuable tools in the management of PML and other JCPyV-related pathology 1.Tan CS, Koralnik IJ. Lancet Neurology 21; 9: Ferenczy MW et al. Clin Microbiol Rev 212;25: Hirsch HH et al. APMIS 213;121:

5 Polyomavirus disease and immune reconstitution In a longitudinal analysis, resolution of viral replication and prevention of disease depends on recovery of BKPyV-specific T-cell immunity: early specific reconstitution does not cause graft inflammatory lesions 1. Hammer MH et al. Am J Transplant 26; 6: Ginevri F et al. Am J Transplant 27; 7:2727. Adoptive T cell therapy: polyomavirus BK BKPyV-specific CTL generated by stimulation with inactivated virus-pulsed DC are able to lyse BKPyV-infected target cells, but are not cytotoxic for uninfected TBE % specific lysis DC auto DC auto BKV DC allo TBE allo CD8 45% HLA-DR 71% CD4 25% CD8/CD56 15% CD56 3% Comoli, et al. J Am Soc Nephrol 23 5

6 Adoptive T cell therapy: polyomavirus BK VP 1 Large T CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL Comoli, et al. J Am Soc Nephrol 23 BKPyV-specific T cell therapy: method 15-mer overlapping peptide library LTag VP1 BKV 6

7 Adoptive T cell therapy: polyomavirus BK % specific lysis Control LT VP1 VP1 LT E:T ratio 5:1 PHA unmanipulated CD4+ CD8+ Evaluation of JCPyV specific immunity in patients with PML IFNγ SFU/1 5 cells VP1 LT PHA 7

8 T cell therapy for PML: JCPyV-specific T-cell lines healthy donor patient with PML T cell therapy for PML: JCPyV-specific T-cell lines 8

9 Allogeneic T cells for JCV-related PML Proliferation cpm JCV peptides 1155 patient PBMC Balduzzi et al. Bone Marrow Transplant 211 Allogeneic T cells for JCV-related PML Proliferation JCV peptides patient PBMC cpm 1155 imatinib budesonide JCV-CTL 5-HT2a cidofovir 1 5 JCV load Balduzzi et al. Bone Marrow Transplant ** days after PML diagnosis JCV DNA CNS JCV DNA blood VP-1 LT MMS score MMS score % lysis 9

10 Allogeneic T cells for JCV-related PML: HSCT Proliferation JCV peptides patient PBMC cpm 1155 imatinib budesonide JCV-CTL 5-HT2a cidofovir 1 5 JCV load Balduzzi et al. Bone Marrow Transplant ** days after PML diagnosis JCV DNA CNS JCV DNA blood VP-1 LT MMS score MMS score % lysis Allogeneic T cells for JCV-related PML: HSCT 1

11 Adoptive T cell therapy: autologous T cells for JCV-related PML T cell therapy for PML: where we stand Preliminary data indicate that it is feasible to expand JCPyV-specific T cell lines from both healthy donors and patients T cell therapy with JCPyV-specific T cell lines may work in the allogeneic and also autologous setting Open questions: optimal composition of cellular product treatment dose/schedule this is important to maximize therapeutic effect while reducing the risk of immune-mediated complications 11

12 T cell therapy for PML: where we stand rapid global recovery of the immune system might not always be favorable: immune reconstitution inflammatory syndrome (IRIS) inflammation can be associated with brain edema, swelling, mass effect, and, in the most severe cases, can cause brain herniation and death IRIS may not be associated to an increase in TH1 responses: No difference in virus-specific IFNγ producing cells between PML-IRIS and pts with PML-S / PML-P / PML-E In serial samples from pts with IRIS in PML, no increase in Th1 response was reported between pre-iris e IRIS peak period The same observations also in the setting of IRIS post-cryptococcosis 1. Gheuens et al. J Virol Chang et al. J Infect Dis Potenza et al. Blood 211; PLOS One 214 Pediatric Hematology/Oncology Fondazione IRCCS Policlinico San Matteo MZecca G Giorgiani F Bonetti N Decembrino T Mina ATolva FCompagno S Recupero S Boghen Cell Factory San Matteo Pavia Comoli s Lab Patrizia Comoli Sabrina Basso Antonella Gurrado Ilaria Pisani Alessandra Maiello Thank you for your attention! 12