Abstract
Metastatic melanoma is an aggressive skin cancer with a relatively low survival rate. Immune-based therapies have shown promise in the treatment of melanoma, but overall complete response rates are still low. Previous studies have demonstrated the potential of plasmid IL-12 (pIL-12) delivered by gene electrotransfer (GET) to be an effective immunotherapy for melanoma. However, events occurring in the tumor microenvironment following delivery have not been delineated. Therefore, utilizing a B16F10 mouse melanoma model, we evaluated changes in the tumor microenvironment following delivery of pIL-12 using different GET parameters or injection of plasmid alone. The results revealed a unique immune cell composition after intratumoral injection of pIL-12 GET. The number of immune memory cells was markedly increased in pIL-12 GET melanoma groups compared to control group. This was validated using flow cytometry to analyze peripheral blood mononuclear cells as well as delineating immune cell content using immunohistochemistry. Significant differences in multiple cell types were observed, including CD8+ T cells, regulatory T cells and myeloid cells, which were induced to mount a CD8+PD1− T cells immune response. Taken together, these findings suggest a basic understanding of the sequence of immune activity following pIL-12 GET and also illuminates that adjuvant immunotherapy can have a positive influence on the host immune response to cancer.
Highlights
Effective treatment options for melanoma are significantly limited, especially for metastatic melanoma and recurrent disease
T cells and myeloid cells, which were induced to mount a CD8+ PD1− T cells immune response. These findings suggest a basic understanding of the sequence of immune activity following plasmid encoding mouse Interleukin 12 (IL-12) (pIL-12) gene electrotransfer (GET) and illuminates that adjuvant immunotherapy can have a positive influence on the host immune response to cancer
Motivated by the synergy observed between expression kinetics and expression levels of IL-12 related to the applied electric pulse parameters in our previous study [10], we explored two different GET treatments, pIL-12 EP1 and pIL-12 EP2
Summary
Effective treatment options for melanoma are significantly limited, especially for metastatic melanoma and recurrent disease. To effectively treat metastatic disease with immunotherapy, it is important to induce a systemic immune response and/or induce memory T cells that can target the primary tumor or recurrences [3]. An alternative strategy to enhance an antitumor immune response is to deliver the cytokine gene directly into tumors. Previous studies have found that IL-12 plasmid delivered by in vivo electroporation (pIL-12 GET) generated successful treatment of established subcutaneous melanoma tumors with minimal to no toxicity in both preclinical and clinical studies [3,8,9,10].
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