Use of Donor T-Lymphocytes Expressing Herpes-Simplex Thymidine Kinase in Allogeneic Bone Marrow Transplantation: A Phase I–II Study. Laboratorie d'Histocompatibilité et Thérapeutique Immuno-Moléculaire, Besançon, France

Tiberghien, Pierre; Cahn, Jean‐Yves; Brion, Annie; Deconinck, Eric; Racadot, E; Hervé, P.; Milpied, Noël; Lioure, Bruno; Gluckman, E.; Bordigoni, Pierre; Jacob, Will; Chiang, Yawen; Marcus, S.; Reynolds, Craig W.; Longo, Dan L.

doi:10.1089/hum.1997.8.5-615

Cited by 80 publications

(39 citation statements)

References 22 publications

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“…In our on-going clinical trial involving the use of HS-tk-expressing donor T cells, CsA treatment might reduce the alloreactive potential of the residual 'fresh' donor T cells infused with the T cell-depleted marrow graft while having no effect on the alloreactivity of the co-administered GCV-sensitive genemodified donor T cells. These findings could be highly relevant for the use of suicide gene-expressing donor T cells 5,27 or other allogeneic T cell-based approaches 28 after allogeneic HSC transplantation.…”

Section: Discussionmentioning

confidence: 86%

“…4 A phase I clinical study evaluating such an approach is underway in our institution. 5 The introduction of the HS-tk gene into donor T cells requires a 12 day ex vivo culture in the presence of IL-2 before infusion with donor hematopoietic stem cells. The 12 day transduction procedure includes a polyclonal (anti-CD3/IL-2) stimulation prior to retrovirus-mediated gene transfer (day 3) followed by a positive selection step (day 5 to 12).…”

Section: Discussionmentioning

confidence: 99%

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Differential effects of cyclosporin A on the alloreactivity of fresh and ex vivo-expanded T lymphocytes

Contassot

Robinet

Angonin

et al. 1998

Bone Marrow Transplant

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Summary:GVHD remains a major source of morbidity and mortality after non-T cell-depleted BMT. The use of donor T lymphocytes expressing a suicide gene could lead to specific immunomodulation after BMT. We are currently evaluating such an approach in a phase I clinical study. A 12-day ex vivo expansion is required to generate gene-modified donor T lymphocytes. CsA is commonly used for GVHD prophylaxis. We analyzed, in a murine GVHD model, the effects of CsA administration on the alloreactivity of fresh or ex vivo-expanded T cells. Variable amounts of fresh or ex vivo-expanded T cells were administered in conjunction with a marrow graft to lethally irradiated allogeneic mice. As expected, a protective effect of CsA with a delayed GVHD-related mortality (P Ͻ 0.01 vs saline treatment) was observed in mice receiving fresh splenocytes. However, CsA treatment had no effect (P = NS) in mice experiencing lethal GVHD induced by ex vivo-expanded T cells whether or not the T cells had been 'rested' in low-dose IL-2 prior to in vivo administration. In agreement with the in vivo findings, CsA also inhibited the in vitro proliferation of alloreactive fresh T cells while having no significant inhibitory effect on the alloreactivity of ex vivoexpanded T lymphocytes. Overall, we demonstrate that the alloreactivity of ex vivo-expanded T lymphocytes is not sensitive to CsA and that this differential effect of CsA is not related to the alloreactive potential of the infused T cells. These findings could be highly relevant when considering allogeneic T cell therapy approaches. Keywords: bone marrow transplantation; cellular therapy; cyclosporin A; alloreactivity; graft-versus-host disease While having beneficial effects on tumor control and engraftment, donor T lymphocytes are responsible for a major complication after allogeneic BMT, namely GVHD. specific ganciclovir (GCV)-induced in vivo T cell depletion if severe GVHD was to occur. 4 A phase I clinical study evaluating such an approach is underway in our institution. 5 The introduction of the HS-tk gene into donor T cells requires a 12 day ex vivo culture in the presence of IL-2 before infusion with donor hematopoietic stem cells. The 12 day transduction procedure includes a polyclonal (anti-CD3/IL-2) stimulation prior to retrovirus-mediated gene transfer (day 3) followed by a positive selection step (day 5 to 12). The gene-modified T cells are then infused to the patient in conjunction with the T cell-depleted bone marrow graft. Cyclosporin A (CsA) is a commonly used immunosuppressive agent in GVHD prophylaxis. 6,7 CsA inhibits IL-2 synthesis, 8 which is one of the first events leading to the proliferation and differentiation of T lymphocytes.The questions we addressed in this study were: does an in vivo CsA treatment for GVHD prophylaxis have comparable effects on the alloreactivity of fresh T lymphocytes vs ex vivo-expanded cells and, if not, what are the consequences of such a differential effect? Materials and methods MiceMale 8-to 12-week-old BALB/c (H-2 d ) and C57BL/6 (B6, ...

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Differential effects of cyclosporin A on the alloreactivity of fresh and ex vivo-expanded T lymphocytes

Contassot

Robinet

Angonin

et al. 1998

Bone Marrow Transplant

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“…Following T cell-depleted BMT, Tiberghien et al 18,21 administered transgenic donor T cells containing the HStk and neo r genes to three patients at high risk for GVHD (unrelated donor or related donor with recipient over 40 years old or female donor to male recipient). 2 × 10 5 gene modified T lymphocytes/kg were infused.…”

Section: Investigator/ref Transgene(s) Hstk Promotor Resultsmentioning

confidence: 99%

“…Several centers have initiated trials using genetically engineered lymphocytes containing the suicide gene, herpes simplex thymidine kinase (HStk). [14][15][16][17][18][19][20][21] Since the HStk death gene is inserted via a retroviral vector, a brief review of retroviral gene therapy follows.…”

mentioning

confidence: 99%

Herpes simplex thymidine kinase (HStk) transgenic donor lymphocytes

Burt

Drobyski

et al. 1999

Bone Marrow Transplant

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Summary:Patients with recurrent leukemia after an allogeneic hematopoietic stem cell transplant may be treated with donor lymphocyte infusions (DLI). The transfusion of lymphocytes from the original hematopoietic stem cell donor induces remission in approximately one third of relapsed AML cases and 80% of relapsed CML. DLI may be complicated by delayed and sometimes lethal graft-versus-host disease (GVHD). In an attempt to avoid this complication, several centers have initiated DLI trials in which the infused lymphocytes carry a suicide gene, herpes simplex thymidine kinase (HStk), which confers sensitivity to ganciclovir (GCV). In the event of severe GVHD, administration of GCV should terminate or ameliorate GVHD. Keywords: donor lymphocyte infusions; retroviral vector; gene therapy In 1990, Kolb et al 1 reported that infusion of lymphocytes from the original bone marrow donor could re-induce remission in patients who relapse after an allogeneic transplant. Subsequently, use of unmanipulated and HStk modified DLI are being evaluated by several investigators. Lymphocytes are generally collected from the peripheral blood of the donor by lymphopheresis, purified by FicollHypaque density gradient centrifugation, and infused as fresh cells into the recipient. Although the effect of cryopreservation on anti-leukemic efficacy is unknown, cells may also be cryopreserved, thawed, and infused at a later date. In general, between 10 6 and 5 × 10 8 T cells per kilogram recipient weight are infused at one time or at intervals of several days to weeks.The optimal dose of donor lymphocytes remains unclear. 22 Although it seems intuitive that larger numbers of infused lymphocytes are more likely to reinduce remission, in an EBMT analysis of 258 patients treated with DLI, patients receiving more than 3.0 × 10 8 mononuclear cells/kg had a lower response rate than those receiving less than 3.0 × 10 8 /kg. 23 This may imply a response plateau or be artifactual since DLI are often given in increments and

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“…6 The use of suicide genes, such as the thymidine kinase from the Herpes Simplex virus (HSV-tk), constitutes a new tool for the management of the GVHD. The transduction of T lymphocytes with this gene turns them susceptible to ganciclovir, allowing the selective elimination of donor T lymphocytes in patients who develop severe episodes of GVHD [7][8][9][10][11][12] In previous studies, we investigated the relevance that several biological parameters had on the generation of human T cells bearing and expressing a transgene of interest. 13 The transduction process included a first step for activating the proliferation of peripheral blood T lymphocytes, a second process of retroviral infection and, finally, a period to facilitate the expression of the selectable transgene.…”

Section: Introductionmentioning

confidence: 99%

Functional and phenotypic variations in human T cells subjected to retroviral-mediated gene transfer

Lamana

Bueren

et al. 2004

Gene Ther

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Use of Donor T-Lymphocytes Expressing Herpes-Simplex Thymidine Kinase in Allogeneic Bone Marrow Transplantation: A Phase I–II Study. Laboratorie d'Histocompatibilité et Thérapeutique Immuno-Moléculaire, Besançon, France

Cited by 80 publications

References 22 publications

Differential effects of cyclosporin A on the alloreactivity of fresh and ex vivo-expanded T lymphocytes

Differential effects of cyclosporin A on the alloreactivity of fresh and ex vivo-expanded T lymphocytes

Herpes simplex thymidine kinase (HStk) transgenic donor lymphocytes

Functional and phenotypic variations in human T cells subjected to retroviral-mediated gene transfer

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