Cytomegalovirus-Specific T Cell Immunotherapy Promotes Restoration of Durable Functional Antiviral Immunity following Allogeneic Stem Cell Transplantation

Clinical Infectious Diseases, Dec 2009

Peggs, Karl S., Verfuerth, Stephanie, Pizzey, Arnold, Chow, Shoon-Ling C., Thomson, Kirsty, Mackinnon, Stephen

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://academic.oup.com/cid/article-pdf/49/12/1851/1200833/49-12-1851.pdf

Cytomegalovirus-Specific T Cell Immunotherapy Promotes Restoration of Durable Functional Antiviral Immunity following Allogeneic Stem Cell Transplantation

Cytomegalovirus-Specific T Cell Immunotherapy Promotes Restoration of Durable Functional Antiviral Immunity following Allogeneic Stem Cell Transplantation Karl S. Peggs 0 Stephanie Verfuerth 0 Arnold Pizzey 0 Shoon-Ling C. Chow 0 Kirsty Thomson 0 Stephen Mackinnon 0 0 Department of Haematology, UCL Medical School, University College London , London , United Kingdom Background. The profound immunodeficiency associated with allogeneic hematopoietic stem cell transplantation is permissive to uncontrolled replication of latent human herpesviridae such as cytomegalovirus. Morbidity and mortality associated with viral dissemination or its treatment are significant. Although adoptive cellular therapy with virus-specific T cells offers the potential for accelerating pathogen-specific immune reconstitution, the risk of induction of graft-versus-host disease and the logistics of production of clonal T cell populations restrict application. Methods. We investigated the ability of cytomegalovirus-specific mixed CD4+ and CD8+ T cell lines, generated by short-term ex vivo culture of donor lymphocytes with donor monocyte-derived dendritic cells pulsed with virus lysate, to restore antiviral immunity in 30 allogeneic transplant recipients at high risk of both uncontrolled viral replication and of graft-versus-host disease. Results. There were no immediate toxicities and no excess of graft-versus-host disease. Massive in vivo expansions of cytomegalovirus-specific T lymphocytes occurred, temporally associating with periods of viral replication, suggesting that antigen exposure was necessary for optimal cytomegalovirus-specific immune reconstitution. The expanding populations maintained functional competence in ex vivo re-stimulation assays, promoting reconstitution of durable functional cytomegalovirus-specific immunity and effectively preventing recurrent viral infection and late cytomegalovirus disease. Conclusions. These data confirm the ability of cellular immunotherapy to hasten reconstitution of antiviral immunity following allogeneic transplantation, indicating that significant clinical benefits may be conferred in terms of reduction of secondary viral infection episodes, potentially reducing exposure to the toxicities of antiviral drugs. Infection with human cytomegalovirus (CMV) is a pomunocompetent individuals. Significant suppression of tentially lethal complication following allogeneic he- - matopoietic stem cell transplantation [ 1 ]. It usually results from reactivation of latent virus and is defined by detection of CMV in peripheral blood samples (usually by polymerase chain reaction). Although reactivation events are probably common during long-term CMV carriage, their detection is relatively uncommon in imhost antiviral immunity, which is affected by both CD8+ and CD4+ T cells, allows reactivation events to become detectable. Uncontrolled viral replication and dissemination can result in the development of end-organ damage (CMV disease). Prophylactic administration of antiviral drugs effectively reduces the incidence of CMV disease following allogeneic hematopoietic stem cell transplantation (HSCT) [ 2, 3 ], but their use is associated with significant morbidity due to suppression of myelopoeisis or induction of renal toxicity. Hence, preemptive rather than prophylactic treatment strategies have generally become routine [4]. These approaches are associated with an increased incidence of late-onset CMV disease [5, 6]. Because the morbidity associated with CMV infec CMV-Specific Immunotherapy after HSCT • CID 2009:49 (15 December) • 1851 tion may be caused either directly by the virus or indirectly through the toxicities associated with antiviral drugs [ 7 ], reduction of drug usage is a valuable therapeutic aim. Furthermore, prior exposure of recipient and/or donor to CMV remains inextricably linked to poor overall survival. This effect seems restricted to recipients of T cell–depleted allografts and/ or transplants from unrelated or human leukocyte antigen (HLA)-mismatched donors [ 7, 8 ]. These considerations have particular current relevance. The increasingly widespread application of reduced intensity conditioning in a more elderly transplant population has been coupled with an expanded use of unrelated donors. Many receive T cell–depleting serotherapy, such as alemtuzumab or ATG, to limit graft-versus-host disease (GvHD). Such patients are at a higher risk of CMV infection and may benefit the most from restoration of anti-CMV immunity, but they are also at greatest risk of GvHD subsequent to infusion of alloreactive T cells. Attempts to restore antiviral immunity following allogeneic HSCT with cell-based immunotherapies initially focused on strategies that required prolonged culture in vitro [ 9, 10 ], and translation into routine clinical practice was limited by the logistics and costs associated with such heroic cell expansions. Subsequent approaches have focused on more rapid gener (...truncated)


This is a preview of a remote PDF: https://academic.oup.com/cid/article-pdf/49/12/1851/1200833/49-12-1851.pdf

Peggs, Karl S., Verfuerth, Stephanie, Pizzey, Arnold, Chow, Shoon-Ling C., Thomson, Kirsty, Mackinnon, Stephen. Cytomegalovirus-Specific T Cell Immunotherapy Promotes Restoration of Durable Functional Antiviral Immunity following Allogeneic Stem Cell Transplantation, Clinical Infectious Diseases, 2009, pp. 1851-1860, Volume 49, Issue 12, DOI: 10.1086/648422