B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma

Abstract

Human hepatocellular carcinoma (HCC) frequently recurs after primary therapy, resulting in poor prognosis. To try to find a way to prevent this, we examined the combined effectiveness of B7‐1 (CD80)‐gene transfer and interleukin‐12 (IL‐12) on the induction of protective antitumor immunity against poorly immunogenic BNL1ME A.7R.1 (BNL) mouse HCC cells. We introduced mouse B7‐1 gene into BNL1ME A.7R.1 cells. Overexpression of B7‐1 on BNL1ME A.7R.1 cells resulted in significant inhibititon of subcutaneous tumor development in syngeneic BALB/c mice, but not in complete rejection, suggesting that strong expression of B7‐1 molecules may enhance the immunogenicity of BNL1ME A.7R.1 cells in immunocompetent mice. Lymphocyte study revealed that the cytolytic activity generated by immunization with B7‐1 transfectants against BNL1ME A.7R.1 cells was mediated mainly by CD8+ cytotoxic T lymphocytes (CTL). We examined the synergistic effect of IL‐12 and immunization with B7‐1 transfectants. The combination led to rejection of BNL1ME A.7R.1 cells in 6 of 10 tested mice and delayed tumor development in the remaining mice. Furthermore, the combined treatment against pre‐established BNL1ME A.7R.1 tumors resulted in rejection in 3 of 8 tested mice or in significant inhibition of tumor growth in the remaining mice. In vivo lymphocyte subset depletion study indicated that the combined antitumor effect was dependent on the presence of both CD8+ and CD4+ T cells. In conclusion, the combination of immunization of B7‐1–transfected HCC cells and IL‐12 could induce protective and therapeutic immunity against parental HCC cells, and this combination may be therapeutically useful for suppressing recurrence of HCC.

Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer

“…40,41 Expression of CD80 was reported to be decreased in the HCC cell lines, 42 and when CD80 was expressed adenovirally, tumor growth was significantly suppressed. 43 However, this effect was fairly weak, so codelivery of CD80 and IL-12 was proposed to enhance antitumor immunity. 43 Furthermore, codelivery of CD80 and HSV-tk was implicated by using adenoassociated virus vector.…”

“…43 However, this effect was fairly weak, so codelivery of CD80 and IL-12 was proposed to enhance antitumor immunity. 43 Furthermore, codelivery of CD80 and HSV-tk was implicated by using adenoassociated virus vector. 44 Interestingly, these data indicate the delivery of the MCP-1 gene induced similar levels of CTL activity in the splenocytes comparable to that observed with the CD80 gene, in which the antigen presentation may be promoted by the recruited macrophages.…”

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

“…Stable expression of Tumor Necrosis Factor Alpha, Interleukin-2, Interleukin-12, Interferon regulatory factor-1 or chimeric cytokines decreases the tumorigenic potential of retrovirally manipulated HCC and, in some instances, induces an immune response against control parental cells implanted in the same animal. 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.…”

“…Gene transfer-mediated expression of B7 molecules has shown reduction of the tumoral size of genetically manipulated cells and induction of an immune response against parental cells that do not express B7. 134 The manipulation of professional antigen-presenting cells such as dendritic cells is considered as a very promising strategy in the treatment of numerous cancers but relies on the characterization of TAA. 137 The transduction of the alpha-fetoprotein gene in dendritic cells, which have been shown to be overexpressed in some HCC, lead to the regression of HCC implanted in the mouse model.…”

Combined IL-12 and GM-CSF gene therapy for murine hepatocellular carcinoma

“…21 -23 This model has a high growth rate and very poor immunogenicity in the syngeneic BALB /c mice, proven to be difficult to treat with a number of conventional as well as gene therapy approaches. 21,23 Likewise, clinical HCCs in human patients exhibit high malignancy, poor immunogenicity, and resistance to a variety of therapeutic modalities. More importantly, HCC is one of the most common cancers, afflicting millions of patients each year with rapid tumor progression and poor clinical prognosis.…”