Irradiated tumor cells adenovirally engineered to secrete granulocyte/macrophage-colony-stimulating factor establish antitumor immunity and eliminate pre-existing tumors in syngeneic mice

Abstract

The specific aim of this study was to examine the prophylactic as well as the therapeutic efficacies of irradiated mouse CT26 colon cancer cells, infected with recombinant adenoviruses harboring cDNAs specific for granulocyte macrophage-colony-stimulating factor (GM-CSF), interferon (IFN-gamma) and monocyte chemotactic protein1 (MCP-1). Results showed that tumor cells secrete the respective cytokines for several days after infection and subsequent irradiation. Vaccination with irradiated GM-CSF-secreting CT26 cells protected 90% of syngeneic mice challenged with live parental cells. On the other hand, vaccination with irradiated IFNgamma or MCP-1-secreting CT26 cells totally failed to protect mice from tumor development after challenge with parental cells. None of the tumor-free mice initially vaccinated with irradiated GM-CSF-producing CT26 cells developed tumor upon repeated challenge with parental cells during the entire observation period. The establishment of specific and long-lasting antitumor immunity following vaccination with GM-CSF-producing tumor cells requires the simultaneous presence of GM-CSF and tumor antigen at the vaccine site. Depletion of CD8+ cells, but not CD4+ cells, blocked the vaccine efficacy of GM-CSF-producing tumor cells. Subcutaneous injection of irradiated GM-CSF-producing CT26 cells also effectively prevented the growth of a small load of parental tumor that was implanted 3 days earlier or the development of metastatic foci in the lung from intravenously injected parental cells either 7 days before or 3 days after vaccination. Our data thus show that, in these experimental tumor models, subcutaneous injection of irradiated tumor cells adenovirally, transduced with the GM-CSF gene leads not only to prevention of growth of subsequently implanted tumor but also to elimination of pre-existing and metastatic tumors.

Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX® vaccine in advanced-stage non-small-cell lung cancer

“…18 Second, an additional advantage of GM-CSF gene-transduced autologous tumor cells over bystander cells may be related to enhanced tumor antigen expression in GM-CSF-transfected cells. 1,3,19,20 Finally, the higher doses of GM-CSF delivered with the bystander GVAX vaccines may have negatively impacted vaccine immunogenicity, owing to induction of myeloid suppressor cells and associated impairment of antigen-specific T-cell responses. Such immunosuppression has been demonstrated in animal studies using high GM-CSF-secreting cellular vaccines.…”

“…Animal studies have consistently demonstrated the safety and antitumor activity of GVAX s vaccines. [1][2][3] Preclinical data also suggest that a threshold of vaccine-associated GM-CSF secretion is necessary to induce optimal antitumor immunity. 4 Clinical trials have been performed in a variety of tumor types, including melanoma, [5][6][7] prostate, 8 renal cell, 9 pancreatic, 10 and lung cancer.…”

Immune-Dependent and Independent Antitumor Activity of GM-CSF Aberrantly Expressed by Mouse and Human Colorectal Tumors

“…This effect of the cytokine on dendritic cells leads to the activation of the immune system against specific antigens (10). Therefore, one approach to cancer immunotherapy is vaccination with tumor-irradiated cells engineered to secrete GM-CSF (6,7,(11)(12)(13). In this context, the action of GM-CSF on dendritic cells allows the immune system to be activated against the specific antigens directly provided by the tumor cells (10).…”

Recombinant Anti-Human HER2/neuIgG3-(GM-CSF) Fusion Protein Retains Antigen Specificity and Cytokine Function and Demonstrates Antitumor Activity

“…However, we do not know the effector mechanism responsible for the antitumor activity of anti-HER2/neu IgG3-(GM-CSF) observed in animals bearing CT26-HER2/neu tumors. Although ADCC mediated by effector cells such as macrophages, eosinophils, and NK cells is a possibility, CD8 ϩ (27) and CD4 ϩ (27,30) cells may also play a role in that they have been shown to be necessary for protection against tumor cell challenge in mice vaccinated with irradiated GM-CSFsecreting tumor cells.…”

“…It is also a potent immunostimulator with pleiotropic effects, including the augmentation of Ag presentation in a variety of cells (17)(18)(19)(20)(21)(22), increased expression of MHC class II on monocytes and adhesion molecules on granulocytes and monocytes (23)(24)(25), and amplification of T cell proliferation (26). In animals, the injection of GM-CSF potentiates the protective effects of an antitumor vaccine by enhancing T cell immunity (26), and vaccination with GM-CSF-transduced cells has been shown to be effective in the treatment of experimental tumors in murine models (27)(28)(29)(30).…”