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Exploiting cytokine secretion to rapidly produce multivirus-specific T cells for adoptive immunotherapy.

ABSTRACT: Viral infections remain a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT), and conventional small-molecule therapeutics often have modest benefit, high cost, and adverse effects. Adoptive transfer of donor-derived virus-specific T cells has proved feasible and safe after HSCT and to reconstitute immunity against cytomegalovirus, Epstein-Barr virus, and adenovirus. Current protocols to generate these cytotoxic T cell lines are lengthy, taking up to 12 weeks. As viral infections often occur <30 days after HSCT, speedy production of virus-specific cytotoxic T cells lacking alloreactivity is highly desirable. We now describe a modified rapid selection method for production and characterization of CD4 and CD8 T cells specific for cytomegalovirus, Epstein-Barr virus, and adenovirus in a single infusate. We use Ad5f35-pp65/latent membrane protein 2 vectors in a single procedure over a 48-hour time period and manufacture a product suited for clinical use. By simultaneously expanding a portion of the selected product, we can characterize phenotype and function of the infused product and link them with subsequent in vivo outcome.

SUBMITTER: Fujita Y

PROVIDER: S-EPMC2643068 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Exploiting cytokine secretion to rapidly produce multivirus-specific T cells for adoptive immunotherapy.

Fujita Yuriko Y Leen Ann M AM Sun Jiali J Nakazawa Yozo Y Yvon Eric E Heslop Helen E HE Brenner Malcolm K MK Rooney Cliona M CM

Journal of immunotherapy (Hagerstown, Md. : 1997) 20080901 7

Viral infections remain a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT), and conventional small-molecule therapeutics often have modest benefit, high cost, and adverse effects. Adoptive transfer of donor-derived virus-specific T cells has proved feasible and safe after HSCT and to reconstitute immunity against cytomegalovirus, Epstein-Barr virus, and adenovirus. Current protocols to generate these cytotoxic T cell lines are lengthy, taking up to 12 w ...[more]

PMID: 18600178

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Project description:BACKGROUNDAdoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications.METHODSWe 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.RESULTSForty 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.CONCLUSIONPersonalized 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 REGISTRATIONNot applicable.FUNDINGThis 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).

Dataset Information

Exploiting cytokine secretion to rapidly produce multivirus-specific T cells for adoptive immunotherapy.

Publications

Exploiting cytokine secretion to rapidly produce multivirus-specific T cells for adoptive immunotherapy.

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