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

Lamana, ML; Bueren, Juan A.; Jl, Vicario; Balas, A.

doi:10.1038/sj.gt.3302188

Cited by 9 publications

(6 citation statements)

References 40 publications

(44 reference statements)

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“…11,12 To determine the relative distribution of memory subsets in human TK ϩ lymphocytes, we analyzed CD45RA/CCR7 coexpression. At day 10, aCD3-TK ϩ lymphocytes were mainly CD45RA Ϫ CCR7 Ϫ EM cells.…”

Section: Cd28 Costimulation Through Cell-sized Beads Generates CM Suimentioning

confidence: 99%

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Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes

Bondanza

Valtolina

Magnani

et al. 2006

Blood

101

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In allogeneic hematopoietic cell transplantation (allo-HCT), the immune recognition of host antigens by donor T lymphocytes leads to a beneficial graft-versus-leukemia (GvL) effect as well as to life-threatening graft-versus-host disease (GvHD). Genetic modification of T lymphocytes with a retroviral vector (RV) expressing the herpes simplex virus-thymidine kinase (TK) suicide gene confers selective sensitivity to the prodrug ganciclovir (GCV). In patients, the infusion of TK ؉ lymphocytes and the subsequent administration of GCV resulted in a time-wise modulation of antihost reactivity for a GvL effect, while controlling GvHD. Because activation required for genetic modification with RV may reduce antihost reactivity, we investigated the requirements for maximizing the potency of human TK ؉ lymphocytes. Whereas T-cell receptor triggering alone led to effector memory (EM)TK IntroductionAllogeneic hematopoietic cell transplantation (allo-HCT) is the curative option for many hematologic malignancies. Moreover, it is being investigated to treat solid tumors. In allo-HCT, the recognition of host antigens by donor T lymphocytes evokes a graft-versusleukemia (GvL) effect. 1 This is associated with the risk of graft-versus-host disease (GvHD). T-cell depletion prevents GvHD but increases the probability of leukemia relapse. Suicide gene therapy offers a pragmatic solution to the "T-cell dilemma" of allo-HCT. 2 A suicide gene codifies for a protein able to convert, at a cellular level, a nontoxic prodrug into a toxic product. Suicide gene modification of donor lymphocytes aims at exploiting allo-HCT for a GvL effect, while providing a selective "switch" to GvHD. 3 The thymidine kinase of herpes simplex virus (TK) is a cell cycledependent suicide gene, that is, it catalyzes the generation of triphosphate ganciclovir (GCV), which is toxic to proliferating cells. 4 In HLA-identical allo-HCT, delayed infusions of TK ϩ lymphocytes were effective against relapsing leukemia, lymphoma, multiple myeloma, and Epstein-Barr virus (EBV)-related lymphoproliferative disorders. 5 When administered at the time of transplantation, TK ϩ lymphocytes facilitated the engraftment of hematopoietic cells. 6,7 In patients developing GvHD, GCV administration eliminated circulating TK ϩ cells and controlled the disease. [5][6][7] Despite these encouraging results, dissemination of the TK technology has been limited by the difficulty in defining optimal conditions for cell manipulation. Current protocols for genetic modification of T lymphocytes with retroviral vectors (RVs) may reduce antigen responsiveness in vitro 8 and antihost reactivity in vivo. 9,10 Given the strict clinical association between GvL and GvHD, it may be postulated that the therapeutic efficacy of TK ϩ lymphocytes will be improved by protocols designed to maximize antihost reactivity in vivo.Genetic modification of T lymphocytes with RVs relies on cell proliferation and leads to a memory phenotype. 11,12 Different models have been proposed to describe mature T-cell differentia...

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Section: Cd28 Costimulation Through Cell-sized Beads Generates CM Suimentioning

confidence: 99%

“…11,12 Different models have been proposed to describe mature T-cell differentiation. The linear model, described first by Sallusto et al in 1999, 13 dictates that antigen exposure control the transition from naive, to central memory (CM) and, eventually, to effector memory (EM) cells.…”

Section: Introductionmentioning

confidence: 99%

Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes

Bondanza

Valtolina

Magnani

et al. 2006

Blood

101

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“…In allogeneic HSCT, suicide gene modification of donor lymphocytes aims at exploiting their GvT effect, while providing a selective “switch” to GvHD ( Bondanza et al, 2005 ). The thymidine kinase of HSV-TK is a cell cycle-dependent suicide gene, that catalyzes the generation of triphosphate ganciclovir (GCV), which is toxic to proliferating cells by inhibiting DNA chain elongation ( Springer and Niculescu-Duvaz, 2000 ; Lamana et al, 2004 ; Bondanza et al, 2006 ). Various clinical studies with HSV-TK transduced donor lymphocyte have been performed and a Phase III multicentric, randomized clinical trial for high-risk acute leukemia is currently undergoing in the context of haploidentical HSCT.…”

Section: Overview Of Cancer Immunotherapy and Cell-based Gene Therapymentioning

confidence: 99%

Improving the safety of cell therapy with the TK-suicide gene

et al. 2015

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While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is allogeneic hematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk hematological malignancies. The potential of allogeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumor effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD). Gene transfer technologies allow to manipulate donor T-cells to enforce GvT and foster immune reconstitution, while avoiding or controlling GvHD. The suicide gene approach is based on the transfer of a suicide gene into donor lymphocytes, for a safe infusion of a wide T-cell repertoire, that might be selectively controlled in vivo in case of GvHD. The herpes simplex virus thymidine kinase (HSV-TK) is the suicide gene most extensively tested in humans. Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug, ganciclovir. Progressive improvements in suicide genes, vector technology and transduction protocols have allowed to overcome the toxicity of GvHD while preserving the antitumor efficacy of allogeneic HSCT. Several phase I-II clinical trials in the last 20 years document the safety and the efficacy of HSV-TK approach, able to maintain its clear value over the last decades, in the rapidly progressing horizon of cancer cellular therapy.

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“…Depending on the clinical setting, gene transfer may target antigen-specific cells, using antigenspecific stimulation, 3 or polyclonal T cells, using mitogens or CD3 antibody-mediated activation. 4 We 5-7 and others [8][9][10][11][12][13][14] have shown both in vitro and in vivo, using murine and canine models of HSC transplantation, that T-cell expansion following stimulation with phytohaemaglutinin (PHA), CD3 or CD3/CD28 is associated with decreased alloreactivity. In particular, we reported that Summary CD3-and CD28-activated T cells expanded for 12 days ex vivo to produce suicide gene-modified T cells are hyporesponsive to alloantigens.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T‐cell expansion and function do not account for the impaired alloreactivity of ex vivo‐expanded T cells

et al. 2008

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

Cited by 9 publications

References 40 publications

Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes

Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes

Improving the safety of cell therapy with the TK-suicide gene

Regulatory T‐cell expansion and function do not account for the impaired alloreactivity of ex vivo‐expanded T cells

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