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Cell Therapy & Immunotherapy
Rapid generation of multivirus-specific T lymphocytes for the prevention and treatment of respiratory viral infections
Ferrata Storti Foundation
Haematologica 2020 Volume 105(1):235-243
Spyridoula Vasileiou, Anne M. Turney, Manik Kuvalekar, Shivani S. Mukhi, Ayumi Watanabe, Premal Lulla, Carlos A. Ramos, Swati Naik, Juan F. Vera, Ifigeneia Tzannou and Ann M. Leen
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, USA
ABSTRACT
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 (ade- novirus) 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 trans- plant 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 immunotherapeu- tic in immunocompromised patients with uncontrolled infections.
Introduction
Acute upper and lower respiratory tract infections (RTI) due to community- acquired respiratory viruses (CARV) including respiratory syncytial virus (RSV), influenza, parainfluenza virus (PIV) and human metapneumovirus (hMPV) are a major public health problem.1 For example, RSV-induced bronchiolitis is the most common reason for hospital admission in children under one year of age,2-4 while the Center for Disease Control (CDC) estimates that, annually, Influenza accounts for up to 35.6 million illnesses worldwide, between 140,000 and 710,000 hospital- izations, annual costs of approximately $87.1 billion in disease management in the US alone, and between 12,000 and 56,000 deaths.
Thus, CARV are a leading cause of morbidity and mortality worldwide, with indi- viduals whose immune systems are naïve (e.g. young children) or compromised being the most vulnerable. For example, in allogeneic hematopoietic stem cell transplant (HSCT) recipients, the incidence of CARV-related respiratory viral diseases is as high as 40%.5 While most patients initially present with rhinorrhea, cough and fever, in approximately 50% of cases, infections progress to the lower respiratory tract and are characterized by severe symptoms including pneumonia and bronchiolitis and mor- tality rates of 23-50%.6-9 There are neither approved preventative vaccines nor antivi- ral drugs for hMPV10 and PIV11 and for Influenza the preventative vaccine is not indi-
Correspondence:
ANN M. LEEN
amleen@txch.org
Received: September 14, 2018. Accepted: April 16, 2019. Pre-published: April 19, 2019.
doi:10.3324/haematol.2018.206896
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1/235
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