Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

BACKGROUND: Adoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications. METHODS: We provide results of a personalized T-cell manufacturing program evaluating donor, patient, T-cell product and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T-lymphocyte (EBV-CTL) products from stem cell donors (SCD), related third party donors (TPD) or unrelated TPD from the allogeneic T-cell donor registry (alloCELL) established at Hannover Medical School were manufactured by immunomagnetic selection using CliniMACS Plus or Prodigy device and EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated and patient outcome and side effects were retrieved by retrospective chart analysis. RESULTS: Forty clinical-grade EBV-CTL products from SCDs, related or unrelated TPDs were generated for 37 patients with and without transplantation (Tx) history within 5 days (median) after donor identification. 34 patients received 1-14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients' blood were detectable in 16/18 monitored patients (89 %) after transfer and correlated with clinical response. CONCLUSION: In conclusion, personalized clinical-grade manufacturing of EBV-CTL products via immunomagnetic selection from SCD, related or unrelated TPD is feasible in a timely manner. Overall, EBV-CTL were clinically effective and well-tolerated. Our data suggest EBV-CTL as promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT as well as patients with pre-existing organ dysfunction

Effective use of high-dose chemotherapy and autologous stem cell rescue for relapsed adult Wilms' tumor and a novel alteration in intron 1 of the WT1 gene

Adult Wilms' tumor (AWT) is a very rare and aggressive malignancy, and little information is available on effective therapy in adults. Although mutations in WT1 have been found in 10% to 15% of childhood Wilms' tumor patients, to date WT1 mutations in AWT patients have not been described. The authors describe a 47-year-old man with relapsed AWT and a novel germline alteration in intron 1 of WT1: IVS1-6 C-->A. This alteration may reduce the splicing efficiency for exon 2 and possibly results in exon skipping. The effective salvage chemotherapy contained ifosfamide, carboplatin, and etoposide and was followed by a high-dose chemotherapy that contained melphalan, carboplatin, and etoposide. Both chemotherapy regimens showed moderate treatment-related toxicity. This report is the first that indicates that adult nephroblastoma patients also may carry WT1 germline mutations

Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course

Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein–Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective, single-center study was undertaken to investigate the impact of therapy on EBV load in adult patients with PTLD. Fifteen patients with PTLD after solid organ transplantation were included and of these, seven had EBV-associated PTLD. All 15 patients received Rituximab as primary therapy. In cases of treatment failure or relapse after Rituximab treatment, patients received polychemotherapy according to the cyclophosphamide, vincristine, doxorubicin, and prednisone regimen. At onset of PTLD, the median EBV load in the peripheral blood of patients was higher in EBV-associated PTLD than PTLD with no associated EBV infection. After Rituximab therapy, four of seven patients with EBV-associated PTLD achieved long-lasting complete remissions. However, in two of these patients, EBV load increased to reach levels as high as those recorded at onset of PTLD. Another patient showed a dramatic decline of EBV load after the first dose of Rituximab while suffering from progressive disease. The other patient relapsed after Rituximab monotherapy, but his viral load stayed low. In total, discordance in EBV load and clinical course was observed in five of the seven patients with EBV-associated PTLD. We conclude that in adult patients with PTLD, EBV load does not correlate with treatment response and is not suitable as a predictive marker for PTLD relapse

Salvage therapy for relapsed posttransplant lymphoproliferative disorders (PTLD) with a second progression of PTLD after upfront chemotherapy: the role of single-agent rituximab

Currently no standard treatment exists for patients with posttransplant lymphoproliferative disorders relapsed or refractory to chemotherapy after failure of reduction in immunosuppression. We have analyzed the effects of single-agent rituximab treatment in eight patients (seven adult, one pediatric) in this setting. Three patients had been salvaged with rituximab several times. In the seven adults, rituximab salvage therapy achieved complete remission (CR) in three patients (43%) and partial remission in one (14%). In the pediatric patient, a PR was obtained that could be reinduced on relapse with repeated administrations of rituximab. Patients achieving CR either remained in CR or were successfully salvaged again with single-agent rituximab. At a median follow-up of 69 months, median progression-free survival was 9 months and no relevant therapy-associated toxicity was observed. Single-agent rituximab salvage therapy is an effective treatment option in this setting of intensively pretreated patients, with virtually no therapy-associated toxicity