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Generation of EBV-specific T-cells using virus-like particles facilitates adoptive treatment of EBV-associated diseases

Reference Number TO 01-00758

Challenge

Epstein-Barr virus (EBV)-specific T-cell lines generated by repeated stimulation with EBV-immortalized lymphoblastoid B-cell lines (LCL) have been successfully used to treat EBV-associated post-transplant lymphoproliferative disease (PTLD) in hematopoetic stem cell transplant recipients. However, because of the laborious and lengthy procedure of preparing EBV-specific T cell lines and the often rapid progression of PTLD, this form of adoptive immunotherapy still has a limited role in the management of virus-associated complications in transplant recipients. To implement this treatment as a conventional and efficacious therapeutic option, generic and more direct approaches for the generation of EBV-specific T-cell lines enriched in disease-relevant specificities need to be developed.

EBV                       Source: NASA
EBV Source: NASA

Technology

CD4+ T cells play an important role in establishing antiviral immunity. In immunosuppressed patients, low numbers of endogenous CD4+ T cells have been identified as risk factor for the development of PTLD. To rapidly generate T-cell lines enriched in EBV-specific CD4+ T cells, the inventors developed a fast and standardized stimulation protocol. Virus-like particles (VLP) of EBV, incapable of transforming primary human B cells, are pulsed onto human PBMC, which are subsequently used to reactivate and expand EBV-specific CD4+ T cells from peripheral blood.

Commercial Opportunity

EBV-VLP stimulated T cells are suggested to be efficient in eliminating newly EBV-infected B cells and thus in controlling EBV infection. A new option to treat EBV-associated diseases like PTLD, nasopharyngeal carcinoma or Hodgkin’s-Disease might approach.

In addition, stimulation with VLP will obviate the lengthy and costly procedure of generating LCL and thus significantly shorten the process of preparing T cells for adaptive T-cell therapy. Furthermore, safety concerns because of EBV wild-type virus in the T cell preparations are no longer an issue.

The technology is available for licensing. Parties interested in collaborative research and development are highly welcomed.

Developmental Status

An in vitro proof-of-concept has been provided demonstrating that EBV-antigen specific CD4+ T cells are efficiently expanded from peripheral blood of EBV-positive donors using PBMC pulsed with EBV-VLP as stimulators. In a PTLD-SCID mouse model, EBV-specific CD4+ T cells delayed tumor growth and prolonged survival as effectively as the CD8+ components.

Patent Situation

A patent is granted in US (US9028840), a EP patent is pending.

Further Reading

Linnerbauer et al. (2014), PLoS Pathog. 10, e1004068; Mautner & Bornkamm (2012), Eur. J. Cell Biol. 91, 31-35; Adhikary et al. (2008), J. Virol. 82, 3903-3911