Adoptive transfer of virus-directed T cells: will this fly for flu?

Abstract

Adoptive transfer of virus-specifi c T cells has been used successfully to prevent and treat severe virus infections in stem cell transplant recipients. In this issue of Cytotherapy, Gaundar et al. (1) describe the possibility of extending the application to infl uenza. Cytomegalovirus (CMV), Epstein–Barr virus (EBV) and adenovirus are three agents that commonly produce morbidity and mortality in immunocompromised patients after stem cell transplantation. All have been controlled effectively by adoptively transferring virus-specifi c T cells generated from donor T lymphocytes by ex vivo culture with live virus or viral antigens (2–4). Protection by these T cells appears to be long lived and mediated by both CD4 and CD8 effector T cells. Gaundar et al. (1) have generated infl uenza virusspecifi c effector T cells using dendritic cells pulsed with commercial inactivated trivalent infl uenza vaccine, a component that will facilitate translation to a clinical protocol. However, a number of potential concerns are introduced by the biology of infl uenza virus and the design of the vaccine. Unlike CMV and EBV, infl uenza is a genetically unstable virus, susceptible to both antigenic drift, involving amino acid changes in immunogenic domains, and genetic shift, involving reassortment of its eight RNA during co-infection of a single cell by two different subtypes (5,6). Such reassortant viruses containing novel combinations of RNA are thought to be the source of major infl uenza pandemics. Vaccines are designed to protect against newly emergent strains and subtypes but elicit non-cross-reactive neutralizing antibodies to the viral hemagglutinin and neuraminidase and are not formulated to elicit T-cell responses in vivo. T cells have the benefi t of recognizing conserved epitopes in viruses, so that natural infection with infl uenza has long been known to induce crossreactive T cells (7–9) that can protect against unrelated subtypes (10). Animal studies have shown that infection with live or live-attenuated viruses are protective or partially protective against multiple strains. However, it is unclear whether virus-specifi c T cells generated in vitro using inactivated viruses would elicit T cells that effectively recognize infections with different infl uenza strains and subtypes. If not, the complexity of any adoptive cell-mediated therapy would greatly increase. Moreover, it is not clear whether T cells alone, even if cross-reactive, will be suffi cient to prevent or clear infl uenza virus in the absence of the strain-specifi c antibodies. Some of these issues are addressed in the current study (1). The investigators pulsed autologous dendritic cells with the trivalent vaccine Fluvax (CSL Laboratories), which contains inactivated A/ California/7/2009-H1N1, A/Wisconsin/15/2009H3N2 and B/Brisbane/60/2008 viruses, and obtained a substantial expansion of polyfunctional infl uenzaspecifi c CD4 and CD8 T cells. These T cells were reactive with all three viruses and had phenotypes indicative of both cytotoxic effector function and the ability to help antibody production. As the T-cell manufacturing process was good manufacturing procedure (GMP)-compliant, in principle these cells could be transferred to stem cell transplant recipients at high risk for disease or suffering from infl uenza infections. Although their results are encouraging, several major questions remain unanswered. For example, we do not yet know whether Fluvax-activated T cells can recognize unrelated strains and subtypes, or if the T-cell donors must be vaccinated or naturally infected Cytotherapy, 2012; 14: 133–134