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      Antiviral T‐cell therapy

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          Summary

          Serious viral infections are a common cause of morbidity and mortality after allogeneic stem cell transplantation. They occur in the majority of allograft recipients and are fatal in 17–20%. These severe infections may be prolonged or recurrent and add substantially to the cost, both human and financial, of the procedure. Many features of allogeneic stem cell transplantation contribute to this high rate of viral disease. The cytotoxic and immunosuppressive drugs administered pretransplant to eliminate the host hematopoietic/immune system and any associated malignancy, the delay in recapitulating immune ontogeny post‐transplant, the immunosuppressive drugs given to prevent graft versus host disease (Gv HD), and the effects of Gv HD itself, all serve to make stem cell transplant recipients vulnerable to disease from endogenous (latent) and exogenous (community) viruses, and to be incapable of controlling them as quickly and effectively as most normal individuals.

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          Most cited references109

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          Inducible apoptosis as a safety switch for adoptive cell therapy.

          Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence. The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
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            HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia.

            In allogeneic bone marrow transplantation (allo-BMT), donor lymphocytes play a central therapeutic role in both graft-versus-leukemia (GvL) and immune reconstitution. However, their use is limited by the risk of severe graft-versus-host disease (GvHD). Eight patients who relapsed or developed Epstein-Barr virus-induced lymphoma after T cell-depleted BMT were then treated with donor lymphocytes transduced with the herpes simplex virus thymidine kinase (HSV-TK) suicide gene. The transduced lymphocytes survived for up to 12 months, resulting in antitumor activity in five patients. Three patients developed GvHD, which could be effectively controlled by ganciclovir-induced elimination of the transduced cells. These data show that genetic manipulation of donor lymphocytes may increase the efficacy and safety of allo-BMT and expand its application to a larger number of patients.
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              How we treat cytomegalovirus in hematopoietic cell transplant recipients.

              Cytomegalovirus (CMV) continues to cause major complications after hematopoietic cell transplantation (HCT). Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. Here, we review aspects of CMV treatment and prevention in HCT recipients, including currently used drugs and diagnostics, ways to optimize preemptive therapy strategies with quantitative polymerase chain reaction assays, the use of prophylaxis, management of CMV disease caused by wild-type or drug-resistant strains, and future strategies.
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                Author and article information

                Journal
                Immunol Rev
                Immunol. Rev
                10.1111/(ISSN)1600-065X
                IMR
                Immunological Reviews
                John Wiley and Sons Inc. (Hoboken )
                0105-2896
                1600-065X
                11 February 2014
                March 2014
                : 258
                : 1 , Transplantation ( doiID: 10.1111/imr.2014.258.issue-1 )
                : 12-29
                Affiliations
                [ 1 ] Center for Cell and Gene Therapy, Baylor College of Medicine Houston Methodist Hospital and Texas Children's Hospital Houston TX USA
                Author notes
                [*] [* ] Correspondence to:

                Ann Leen

                Center for Cell and Gene Therapy

                Baylor College of Medicine

                1102 Bates Street, Suite 1780.06

                Houston, TX 77030, USA

                Tel.: +1 832 824 4690

                Fax: +1 832 825 4732

                e‐mail: amleen@ 123456txch.org

                Article
                IMR12138
                10.1111/imr.12138
                3927231
                24517423
                f7d0eab5-45c3-4fd8-8e83-80b8031f0317
                © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                Page count
                Pages: 18
                Funding
                Funded by: NIH
                Award ID: P50CA126752
                Award ID: PO1CA94237
                Award ID: U54HL081007
                Award ID: N01‐HB‐10‐03
                Funded by: Production Assistance for Cellular Therapies
                Award ID: HHSN268201000007C
                Funded by: Dan L. Duncan Cancer Center
                Award ID: P30CA125123
                Categories
                Invited Review
                Invited Reviews
                Custom metadata
                2.0
                March 2014
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                t cells,immunotherapies,transplantation
                t cells, immunotherapies, transplantation

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