4.4 Article

Rapid generation of multivirus-specific T lymphocytes for the prevention and treatment of respiratory viral infections

Journal

HAEMATOLOGICA
Volume 105, Issue 1, Pages 235-243

Publisher

FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.206896

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Funding

  1. Flow Cytometry and Cell and Vector Production shared resources in the Dan L. Duncan Comprehensive Cancer Center [P30 CA125123]
  2. Hellenic Foundation of Hematology
  3. American Society of Hematology Junior Faculty Scholar grant
  4. Leukemia Texas Research grant
  5. Mentored Research Scholars Grant in Applied and Clinical Research from the American Cancer Society [MRSG-14-197-01-LIB]

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Respiratory tract infections due to community-acquired respiratory viruses including respiratory syncytial virus, Influenza, parainfluenza virus 3 and human metapneumovirus are detected in up to 40% of allogeneic hematopoietic stem cell transplant recipients in whom they cause severe symptoms including pneumonia and bronchiolitis and can be fatal. Given the lack of effective antivirals and the data from our group demonstrating that adoptively transferred ex vivo-expanded virus-specific T cells can be clinically beneficial for the treatment of both latent (Epstein-Barr virus, cytomegalovirus, BK virus, human herpesvirus 6) and lytic (adenovirus) viruses, we investigated the potential for extending this immunotherapeutic approach to respiratory viruses. We now describe a system that rapidly generates a single preparation of polyclonal (CD4(+) and CD8(+)) virus-specific T cells reactive against 12 antigens derived from four viruses (respiratory syncytial virus, Influenza, parainfluenza virus 3 and human metapneumovirus) that commonly cause post-transplant morbidity and mortality. With a single in vitro stimulation we consistently generated Th1-polarized T-cell lines that produced multiple effector cytokines and were selectively reactive against viral-expressing targets, with no evidence of off target auto- or allo-reactivity. Finally, we demonstrated the clinical relevance of these virus-specific T cells by measuring responses in transplant recipients who successfully controlled active infections. These results support the clinical importance of T-cell immunity in mediating protective antiviral effects against community-acquired respiratory viruses and demonstrate the feasibility of utilizing a broad-spectrum immunotherapeutic in immunocompromised patients with uncontrolled infections.

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