Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by cDNA-transfected tumor cells induces a more potent antitumor response than exogenous GM-CSF

Abstract

Clinical cancer gene therapy trials have generally focused on the transfer of cytokine cDNA to tumor cells ex vivo and with the subsequent vaccination of the patient with these genetically altered tumor cells. This approach results in high local cytokine concentrations that may account for the efficacy of this technique in animal models. We hypothesized that the expression of certain cytokines by tumor cells would be a superior immune stimulant when compared with local delivery of exogenous cytokines. Granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA in a nonviral expression vector was inserted into MDA-MB-231 (human breast cancer), M21 (human melanoma), B16 (murine melanoma), and P815 (mastocytoma) cells by particle-mediated gene transfer. The ability of transfected tumor cells to generate a tumor-specific immune response was evaluated in an in vitro mixed lymphocyte-tumor cell assay and in an in vivo murine tumor protection model. Peripheral blood lymphocytes cocultured with human GM-CSF-transfected tumor cells were 3-to 5-fold more effective at lysis of the parental tumor cells than were peripheral blood lymphocytes incubated with irradiated tumor cells and exogenous human GM-CSF. Mice immunized with murine GM-CSF-transfected irradiated B16 murine melanoma cells or P815 mastocytoma cells were protected from subsequent tumor challenge, whereas mice immunized with the nontransfected tumors and cutaneous transfection of murine GM-CSF cDNA at the vaccination site developed tumors more frequently. The results indicate that GM-CSF protein expressed in human and murine tumor cells is a superior antitumor immune stimulant compared with exogenous GM-CSF in the tumor microenvironment.

Highly Successful Therapeutic Vaccinations Combining Dendritic Cells and Tumor Cells Secreting Granulocyte Macrophage Colony-stimulating Factor

“…Indeed, the more toxic the treatment the less the secretion of GM-CSF by the transduced tumor cells and the worse the therapeutic response observed. Moreover, in agreement with the work of Shi et al (35) but contrary to Kurane et al (36), we observed that the GM-CSF protein expressed by tumor cells after gene transfer was a superior stimulant than exogenous GM-CSF given in the tumor microenvironment by repeated injections or osmotic minipumps (8). This could be explained in part by the short half-life (few hours) of recombinant GM-CSF (37).…”

Chitosan hydrogel containing GMCSF and a cancer drug exerts synergistic anti-tumor effects via the induction of CD8+ T cell-mediated anti-tumor immunity

“…Thus, frequent or continuous cytokine administration would be required at the immunization sites in order to overcome these limitations, and is expected to result in a dissimilar pharmacokinetic profile and a less durable effect than cytokine-secreting hydrogel with steady secretion. There have been some reports which have demonstrated that immunization with GMCSF-secreting cells yielded superior anti-tumor efficacy, as compared to the co-administration of rGMCSF and irradiated, non-cytokine secreting cells [36,37].…”

Carrier Cell–mediated Delivery of a Replication-competent Adenovirus for Cancer Gene Therapy

“…Clinical trials have revealed clear anti-tumor and immuno-modulating effects of GM-CSF gene therapy in treating renal cell carcinoma, melanoma, lung cancer, bladder cancer, and hematological malignancies. [20][21][22] GM-CSF-secreting tumor cells have been found to stimulate potent, specific, and long-lasting anti-tumor immunity, partly because GM-CSF stimulates the proliferation and differentiation of antigen-presenting cells. 23,24 Although the anti-tumor effects of GM-CSF alone were insufficient to eradicate tumors, our carrier cell experiments demonstrated that animals could be completely cured with injection of carrier cells co-infected with AdE3-IAI.3B and AxCAmGM-CSF after immunization with adenovirus.…”