Lymphodepletion followed by infusion of suicide gene-transduced donor lymphocytes to safely enhance their antitumor effect: a phase I/II study

Maury, Sébastien; Rosenzwajg, Michèlle; Redjoul, Rabah; Marçais, Ambroise; Xhaard, Aliénor; Cheraï, Mustapha; Cabanne, Ludovic; Churlaud, Guillaume; Suarez, Félipe; Socié, Gérard; Grégoire, L; Debbache, Karima; Bernard, Carole; Jl, Beaumont; Azar, Nabih; Boyer, Olivier; Roudot‐Thoraval, Françoise; Cohen, José L.; Cordonnier, Catherine; Fm, Lemoine; Klatzmann, David

doi:10.1038/leu.2014.237

Cited by 15 publications

(12 citation statements)

References 15 publications

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“…Notably, patients with metastatic melanoma treated with denileukin diftitox showed no clinical benefit and severe autoimmune side effects 251 . Depletion of T reg cells from HSCT to treat relapses of leukaemia in patients who did not develop GVHD during the first transplant produced better outcomes 252 . These data suggest that global T reg cell depletion has variable efficacy and the potential to induce systemic complications.…”

Section: T Reg Cell Depletionmentioning

confidence: 99%

Regulatory T cells in the treatment of disease

Sharabi

Tsokos

Ding

et al. 2018

Nat Rev Drug Discov

242

206

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| Regulatory T (T reg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, T reg cells are compromised. Approaches to strengthen T reg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing T reg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, T reg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of T reg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating T reg cells in autoimmune disorders, transplantation and cancer.

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Section: T Reg Cell Depletionmentioning

confidence: 99%

Regulatory T cells in the treatment of disease

Sharabi

Tsokos

Ding

et al. 2018

Nat Rev Drug Discov

242

206

View full text Add to dashboard Cite

show abstract

“…Many studies also have achieved good results in the application of suicide gene system in multiple malignancy tumors, such as glioblastoma, prostate cancer, and breast cancer (21)(22)(23). Moreover, some clinical trial of suicide gene therapy for patients with certain malignant tumors showed encouraging effects (24,25). However, the efficacy of the suicide gene therapy for the treatment of cancer is limited because of the low killing activity.…”

Section: Discussionmentioning

confidence: 99%

All-trans retinoic acid enhances bystander effect of suicide gene therapy in the treatment of breast cancer

et al. 2015

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All-trans retinoic acid (ATRA) has been shown to enhance the expression of connexin 43 (Cx43) and the bystander effect (BSE) in suicide gene therapy. These in turn improve effects of suicide gene therapies for several tumor types. However, whether ATRA can improve BSE remains unclear in suicide gene therapy for breast cancer. In the present study, MCF-7, human breast cancer cells were treated with ATRA in combination with a VEGFP-TK/CD gene suicide system developed by our group. We found that this combination enhances the efficiency of cell killing and apoptosis of breast cancer by strengthening the BSE in vitro. ATRA also promotes gap junction intercellular communication (GJIC) in MCF-7 cells by upregulation of the connexin 43 mRNA and protein in MCF-7 cells. These results indicate that enhancement of GJIC by ATRA in suicide gene system might serve as an attractive and cost-effective strategy of therapy for breast cancer cells.

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“…In the presence of ganciclovir (GCV), an anti-herpes drug, infected cells catalyze the generation of triphosphate ganciclovir that further inhibits DNA chain elongation, which is toxic to proliferating cells (89,90). In-vitro and in-vivo preclinical studies in mice (91,92) and afterward phase I/II clinical trials have demonstrated that the retroviral-mediated transfer of HSV-TK suicide gene into donor T cells prior to graft infusion allows efficient control of donor T cell alloreactivity (93,94). In the latter clinical trial, the investigators also showed that these infected T cells improve immune reconstitution and could provide GVL effect.…”

Section: Gene Therapy Of Agvhdmentioning

confidence: 99%

Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies

et al. 2020

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Graft versus host disease (GVHD) is one of the main causes of mortality and the reason for up to 50% of morbidity after hematopoietic stem cell transplantations (HSCT) which is the treatment of choice for many blood malignancies. Thanks to years of research and exploration, we have acquired a profound understanding of the pathophysiology and immunopathology of these disorders. This led to the proposition and development of many therapeutic approaches during the last decades, some of them with very promising results. In this review, we have focused on the recent GVHD treatments from classical chemical and pharmacological prophylaxis to more innovative treatments including gene therapy and cell therapy, most commonly based on the application of a variety of immunomodulatory cells. Furthermore, we have discussed the advantages and potentials of cell-free therapy as a newly emerging approach to treat GVHD. Among them, we have particularly focused on the implication of the TNFα-TNFR2 axis as a new immune checkpoint signaling pathway controlling different aspects of many immunoregulatory cells.

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Lymphodepletion followed by infusion of suicide gene-transduced donor lymphocytes to safely enhance their antitumor effect: a phase I/II study

Cited by 15 publications

References 15 publications

Regulatory T cells in the treatment of disease

Regulatory T cells in the treatment of disease

All-trans retinoic acid enhances bystander effect of suicide gene therapy in the treatment of breast cancer

Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies

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