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

Abstract

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 (SCDs), related third-party donors (TPDs), or unrelated TPDs from the allogeneic T cell donor registry (alloCELL) at Hannover Medical School were manufactured by immunomagnetic selection using a CliniMACS Plus or Prodigy device and the 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 TPDs, or unrelated TPDs were generated for 37 patients with refractory EBV infections or EBV-associated malignancies with and without a history of transplantation, within 5 days (median) after donor identification. Thirty-four patients received 1–14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to a 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 of 18 monitored patients (89%) after transfer, and their presence correlated with clinical response. CONCLUSION Personalized clinical-grade manufacture of EBV-CTL products via immunomagnetic selection from SCDs, related TPDs, or unrelated TPDs in a timely manner is feasible. Overall, EBV-CTLs were clinically effective and well tolerated. Our data suggest EBV-CTL transfer as a promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT, as well as patients with preexisting organ dysfunction. TRIAL REGISTRATION Not applicable. FUNDING This study was funded in part by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), Wilhelm-Sander-Stiftung (reference 2015.097.1), Ellen-Schmidt-Program of Hannover Medical School, and German Federal Ministry of Education and Research (reference 01EO0802).

Virus-specific T-cells from third party or transplant donors for treatment of EBV lymphoproliferative diseases arising post hematopoietic cell or solid organ transplantation

“…The number of virus-specific T-cells within the fixed doses of EBVCTLs administered, which have ranged from 2-6 x 10 7 /m 2 ( 11 , 27 , 44 – 47 ) have also not distinguished responder from non-responder cohorts. Furthermore, high response rates have been observed even in trials of IFNγ-secreting EBVCTLs separated directly from leukaphereses in which mean doses of only 1.5 x10 5 /m 2 are administered ( 38 ).…”

“…Historically, 3 rd party EBVCTLs have been selected by choosing EBVCTLs that share the most class I HLA alleles with the patient ( 28 , 38 , 48 ). In SOT patients, this approach has usually worked for two reasons: 1) The EBV+ lymphoma is of patient origin in over 90% of cases ( 41 ) and 2) as noted previously, the most immunogenic epitopes of the EBV latency proteins are usually presented by a relatively limited number of prevalent HLA alleles, permitting selection of a partially HLA-matched 3 rd party EBVCTL with a high likelihood of activity from a limited bank of seropositive donors most of whom will inherit one or more of the prevalent alleles ( 49 ).…”

Protective function ofex vivoexpanded CD8 T cells in a mouse model of adoptive therapy for cytomegalovirus infection depends on integrin beta 1 but not CXCR3, CTLA4, or PD-1 expression

“…13,18 One strategy for ATCT generation for the treatment of viral diseases is to identify and select VST from the donor blood directly using specific peptide-MHC class I complexes 19,20 or cytokine capture systems. 17,[21][22][23][24] The second strategy relies on the selective VST expansion after ex vivo stimulation of donor leukocytes with antigen-presenting cells presenting viral peptides or proteins. 16,[25][26][27][28] Ex vivo expansion protocols are also the basis for genetic engineering approaches, which are particularly interesting as they hold promise to develop VSTs resistant to immunosuppressive drugs, [29][30][31] or to bypass MHC-restriction by producing virus-specific TCR-transgenic T cells 32 and CAR-T cells.…”

“…13 Hence, the reconstitution of the antiviral immunity by adoptive transfer of donor-derived virus-specific T cells (VSTs) is an attractive alternative treatment strategy in hematopoietic stem cell transplant patients and is also considered for solid organ transplant recipients. 11–17…”

Conference Report 33rd European Congress on Clinical Microbiology and Infectious Diseases (ECCMID): New developments in pediatric oncology infectious disease supportive care

“…Contributions at this year's ECCMID centered around two important topics: the radiographic presentation, the epidemiology, and the prevention of IFDs and reports on the approaches of individual centers to the de‐escalation of antibacterial therapy of fever of unknown origin in neutropenic patients. Other topics that were not represented but are challenging for all infectious disease specialists involved in pediatric cancer and HCT patients include the non‐pharmacological approaches to infection prevention, antibacterial prophylaxis, hospital epidemiology and control of resistant bacterial and fungal pathogens, the impact of alterations in the intestinal microbiome, the complex issue of respiratory viral infections in this population, new approaches to prevention and treatment of systemic viral infections, potential consequences of climate changes on the spectrum of potential pathogens, and the impact of replacements of conventional cancer chemotherapies by immunologically based approaches 31–39 …”