Abstract
A successful DNA vaccine for the treatment of tumors should break established immune tolerance to tumor antigen. However, due to the relatively low immunogenicity of DNA vaccines, compared to other kinds of vaccines using live virus or protein, a recombinant viral vector was used to enhance humoral and cellular immunity. In the current study, we sought to develop a novel anti-cancer agent as a complex of DNA and oncolytic adenovirus for the treatment of malignant melanoma in the C57BL/6 mouse model. MART1, a human melanoma-specific tumor antigen, was used to induce an increased immune reaction, since a MART1-protective response is required to overcome immune tolerance to the melanoma antigen MelanA. Because GM-CSF is a potent inducer of anti-tumor immunity and TGF-β2 is involved in tumor survival and host immune suppression, mouse GM-CSF (mGM-CSF) and shRNA of mouse TGF-β2 (shmTGF-β2) genes were delivered together with MART1 via oncolytic adenovirus. MART1 plasmid was also used for antigen-priming. To compare the anti-tumor effect of oncolytic adenovirus expressing both mGM-CSF and shmTGF-β2 (AdGshT) with that of oncolytic adenovirus expressing mGM-CSF only (AdG), each virus was intratumorally injected into melanoma-bearing C57BL/6 mice. As a result, mice that received AdGshT showed delayed tumor growth than those that received AdG. Heterologous prime-boost immunization was combined with oncolytic AdGshT and MART1 expression to result in further delayed tumor growth. This regression is likely due to the following 4 combinations: MART1-derived mouse melanoma antigen-specific immune reaction, immune stimulation by mGM-CSF/shmTGF-β2, tumor growth inhibition by shmTGF-β2, and tumor cell-specific lysis via an oncolytic adenovirus. Immune activation was mainly induced by mature tumor-infiltrating dendritic cell (TIDC) and lowered regulatory T cells in tumor-infiltrating lymphocytes (TIL). Taken together, these findings demonstrate that human MART1 induces a mouse melanoma antigen-specific immune reaction. In addition, the results also indicate that combination therapy of MART1 plasmid, together with an oncolytic adenovirus expressing MART1, mGM-CSF, and shmTGF-β2, is a promising candidate for the treatment of malignant melanoma.
Highlights
The incidence of malignant melanoma is increasing worldwide [1], and is the fifth highest incidence among cancers in the US and the UK [2]
Granulocytemacrophage colony-stimulating factor (GM-CSF), short hairpin RNA (shRNA) against transforming growth factor-β (TGF-β), and melanoma antigen recognized by T cells 1 (MART1) were administered to mice to determine the effectiveness of immunotherapy as a complex form of DNA vaccine and armed oncolytic adenovirus on melanoma
To overcome this issue and induce an anti-B16BL6 tumor immune response, human MART1 plasmid was administered to mice as a DNA vaccine
Summary
The incidence of malignant melanoma is increasing worldwide [1], and is the fifth highest incidence among cancers in the US and the UK [2]. Early primary melanomas can be cured surgically, this cancer can rapidly become fatal, following the development of metastasis. Therapeutic agents such as ipilimumab, which targets the cytotoxic T lymphocyte-associated protein 4 (CTLA4), and vemurafenib, which targets mutations that activate the B- Rapidly Accelerated Fibrosarcoma (RAF) gene, have previously been developed for malignant melanoma. While these agents take a short amount of time to respond to treatment, they lack high cure rates [3,4,5,6]. Granulocytemacrophage colony-stimulating factor (GM-CSF), shRNA against transforming growth factor-β (TGF-β), and melanoma antigen recognized by T cells 1 (MART1) were administered to mice to determine the effectiveness of immunotherapy as a complex form of DNA vaccine and armed oncolytic adenovirus on melanoma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
