Use of suicide gene‐expressing donor T‐cells to control alloreactivity after haematopoietic stem cell transplantation

Tiberghien, Pierre

doi:10.1046/j.1365-2796.2001.00809.x

Cited by 33 publications

(14 citation statements)

References 43 publications

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“…Data from both mouse and human allogeneic studies have shown that donor T cells exhibit decreased allo-reactivity and GVHD potential following ex vivo activation and expansion [2][3][4][5][6]. This loss of allo-reactivity is extremely undesirable because both the conversion to full donor chimerism and the anti-leukemia effect after allogeneic HSCT are mediated, at least in part, by alloreactive donor T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Many of the therapeutic strategies that are being developed to control GVHD while maintaining the beneficial graft-versus-leukemia and/or graft-versus-infection effects provided by donor lymphocyte infusion after allogeneic HSCT require ex vivo T cell stimulation and expansion. Unfortunately, multiple preclinical and clinical studies have demonstrated that these ex vivo expanded T cells exhibit decreased survival and function in vivo, including reduced alloreactivity and GVHD potential [2][3][4][5][6]. Recently, others and we described an ex vivo method for expansion of human T (huT) cells, using anti-CD3 and anti-CD28 monoclonal antibodies that are covalently attached to superparamagnetic microbeads (CD3/CD28 beads) [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi

Rettig

Ritchey

et al. 2007

Experimental Hematology

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Objective-Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Models of immunodeficient mice that consistently and efficiently reconstitute with xenoreactive human T cells would be a valuable tool for the in vivo study of GVHD, as well as other human immune responses.Materials and Methods-We developed a consistent and sensitive model of human GVHD by retro-orbitally injecting purified human T cells into sublethally irradiated NOD/SCID-β2m null recipients. In addition, we characterized for the first time the trafficking patterns and expansion profiles of xenoreactive human T cells in NOD/SCID-β2m null recipients using in vivo bioluminescence imaging.Results-All NOD/SCID-β2m null mice conditioned with 300 cGy of total body irradiation and injected with 1 × 10 7 human T cells exhibited human T cell engraftment, activation, and expansion, with infiltration of multiple target tissues and a subsequent greater than 20% loss of pretransplant body weight. Importantly, histological examination of the GVHD target tissues revealed changes consistent with human GVHD. Furthermore, we also showed by in vivo bioluminescence imaging that the development of lethal GVHD in the NOD/SCID-β2m null recipients was dependent upon the initial retention and early expansion of human T cells in the retroorbital sinus cavity.Conclusion-Our NOD/SCID-β2m null mouse model provides a system to study the pathophysiology of acute GVHD induced by human T cells and aids in the development of more effective therapies for human GVHD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi

Rettig

Ritchey

et al. 2007

Experimental Hematology

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“…5,6 Although the genetic modification of donor lymphocytes to introduce suicide genes may improve the safety profile of DLIs by rendering transferred lymphocytes susceptible to in vivo ablation, the low potency and high association with GVHD continue to be major obstacles to achieving clinically robust anti-B-ALL GVL augmentation by this approach. [7][8][9] Adoptive transfer of donor-derived T cells having antigen specificity restricted to the leukemic clone itself or to target antigens selectively expressed by host hematopoietic lineage cells has the potential to selectively augment GVL without exacerbating GVHD. Minor histocompatibility antigens (mHags) encoded by polymorphic genes selectively expressed in recipient leukemic cells/hematopoietic-derived cells can serve as target antigens for donor T cells and mediate selective tumor eradication.…”

Section: Introductionmentioning

confidence: 99%

T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B–lineage leukemia effect

Cooper

Topp

Serrano

et al. 2003

Blood

232

206

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Relapse of B-lineage acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (HSCT) commonly results from the failure of a graft-versus-leukemia (GVL) effect to eradicate minimal residual disease. Augmenting the GVL effect by the adoptive transfer of donor-derived B-ALL-specific T-cell clones is a conceptually attractive strategy to decrease relapse rates without exacerbating graft-versus-host disease (GVHD). Toward this end, we investigated whether a genetic engineering approach could render CD8 ؉ cytotoxic T lymphocytes ( 1 (LFA-1), and LFA-3. We observed that recognition of B-lineage tumor lines by CD19-specific CTLs was not impaired by low levels of ICAM-1, LFA-1, and LFA-3 cell surface expression, a functional attribute that is likely a consequence of our high-affinity CD19-specific chimeric immunoreceptor. Furthermore, the CD19-specific CTLs could lyse primary B-ALL blasts. These preclinical observations form the basis for implementing clinical trials using donor-derived CD19-specific T-cell clones to treat or prevent relapse of B-ALL after alloge-

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“…Simple or nested PCR for retroviral-carried transgenes NeoR and HSV-tk was performed on posttransplantation PBMCs, G418-selected GMCs, and cloned T cells, as previously described. 14,36 This enabled screening of resistant G418 T-cell clones obtained after G418-mediated reselection of GMCs, and identification of both wild-type (functional) and truncated (nonfunctional) forms of the HSV-tk gene.…”

Section: Ex Vivo Reselection and Cloning Of Circulating Gmcsmentioning

confidence: 99%

Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft

Deschamps

Mercier-Lethondal

Certoux

et al. 2007

Blood

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In our previous phase 1/2 study aimed at controlling graft-versus-host disease, 12 patients received Herpes simplex virus thymidine kinase (HSV-tk ؉ )/ neomycin phosphotransferase (NeoR ؉ )-expressing donor gene-modified T cells (GMCs) and underwent an HLA-identical sibling T-cell-depleted bone marrow transplantation (BMT). This study's objective was to follow up, to quantify, and to characterize persistently circulating GMCs more than 10 years after BMT. Circulating GMCs remain detectable in all 4 evaluable patients. However, NeoRand HSV-tk-polymerase chain reaction

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Use of suicide gene‐expressing donor T‐cells to control alloreactivity after haematopoietic stem cell transplantation

Cited by 33 publications

References 43 publications

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B–lineage leukemia effect

Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft

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