GM-CSF-secreting cancer immunotherapies: preclinical analysis of the mechanism of action |
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Authors: | Andrew D Simmons Betty Li Melissa Gonzalez-Edick Carol Lin Marina Moskalenko Thomas Du Jennifer Creson Melinda J VanRoey Karin Jooss |
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Institution: | (1) Cell Genesys Inc., 500 Forbes Blvd., South San Francisco, CA 94080, USA |
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Abstract: | Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapies have demonstrated long-lasting,
and specific anti-tumor immune responses in animal models. The studies reported here specifically evaluate two aspects of
the immune response generated by such immunotherapies: the persistence of irradiated tumor cells at the immunization site,
and the breadth of the immune response elicited to tumor associated antigens (TAA) derived from the immunotherapy. To further
define the mechanism of GM-CSF-secreting cancer immunotherapies, immunohistochemistry studies were performed using the B16F10
melanoma tumor model. In contrast to previous reports, our data revealed that the irradiated tumor cells persisted and secreted
high levels of GM-CSF at the injection site for more than 21 days. Furthermore, dense infiltrates of dendritic cells were
observed only in mice treated with GM-CSF-secreting B16F10 cells, and not in mice treated with unmodified B16F10 cells with
or without concurrent injection of rGM-CSF. In addition, histological studies also revealed enhanced neutrophil and CD4+ T
cell infiltration, as well as the presence of apoptotic cells, at the injection site of mice treated with GM-CSF-secreting
tumor cells. To evaluate the scope of the immune response generated by GM-CSF-secreting cancer immunotherapies, several related
B16 melanoma tumor cell subclones that exist as a result of genetic drift in the original cell line were used to challenge
mice previously immunized with GM-CSF-secreting B16F10 cells. These studies revealed that GM-CSF-secreting cancer immunotherapies
elicit T cell responses that effectively control growth of related but antigenically distinct tumors. Taken together, these
studies provide important new insights into the mechanism of action of this promising novel cancer immunotherapy.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Cancer immunotherapy Tumor immunology Granulocyte-macrophage colony-stimulating factor Dendritic cells |
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