A “Distant” Bystander Effect of Suicide Gene Therapy: Regression of Nontransduced Tumors Together with a Distant Transduced Tumor

Abstract

Antitumor gene therapy using herpes simplex type 1 thymidine kinase (TKh) and ganciclovir (GCV) treatment has revealed an important intratumoral bystander effect. A whole tumor can be eliminated when only a fraction of its tumor cells express TKh. We now report that the bystander effect not only acts within a tumor, but also between distant tumors. One TKh+ tumor was generated simultaneously with one or multiple TKh- tumors in different rat liver lobes such that there was no contact between the resulting tumors. Both the TKh+ and the TKh- tumors regressed after GCV treatment and showed infiltration with macrophages and T lymphocytes. This distant bystander effect, which is likely immune mediated, should be of major importance for gene therapy of disseminated tumors.

Combined suicide and granulocyte–macrophage colony-stimulating factor gene therapy induces complete tumor regression and generates antitumor immunity

“…1,18,19 Several studies have demonstrated the immunological component of the bystander effect. Nude mice are impaired in their ability to effect suicide gene -mediated tumor regression, 8,12 treatment generates systemic antitumor immunity, 8,20,21 and tumor regression is associated with a significant leukocytic infiltrate 11,19,22,23 and cytokine release. 19,23,24 Other therapeutic approaches being considered involve the transfer of cytokine genes into tumor cells.…”

Connexin 26 enhances the bystander effect in HSVtk/GCV gene therapy for human bladder cancer by adenovirus/PLL/DNA gene delivery

“…35,36 The induced immunogenicity to distant HSVtk-negative tumor cells has been termed the distant bystander effect. 37,38 When cells become transformed, the expression of functional gap junctions decreases. 10 Cx transfection and GJIC induction lead to a decreased rate of proliferation, increased differentiation, and reversal of the cell-transformation phenotype.…”

Gene therapy of hepatocarcinoma: a long way from the concept to the therapeutical impact

“…In some immunocompetent animal models of HCC, a distant bystander effect relying on the activation of the immune system has been described, which synergizes with the direct elimination of tumor cells. [114][115][116][117] HSV-TK/GCV treatment has been extensively experienced in vitro and in animal models either with tumors obtained following injection of HCC lines or chemically induced HCC as shown in DEN-induced HCC in the rat model. 104,118 In this last model, using adenoviral vectors to transfer the HSV-TK gene, we have shown that a unique intratumoral injection of the viral vector with daily administration of GCV allows strong reductions of large-size tumors.…”

“…77,[129][130][131][132][133][134] The HSV-TK/GCV treatment has also been shown to correlate with the induction of an immune response against tumor cells called the ''distant bystander effect'' that induces the regression of orthotopic HCC tumors at a distant site from the reinjected tumor. 116 Transfer of immunomodulatory cytokines such as Interleukin-12 and GM-CSF or the recruitment of accessory cells with the chemoattractant protein-1 has been proposed to potentiate the antitumor effect of the HSV-TK/GCV treatment. 130,135,136 Several mechanisms have been reported to explain the low immunogenic potential or the absence of immune recognition of the tumor cells including the lack of expression of the Major Histocompatibility Complex B7 molecule at the membrane of the tumor cells.…”