Abstract
Immune escape of tumor cells is one of the main obstacles hindering the effectiveness of cancer immunotherapy. We developed a novel strategy to block immune escape by transfecting tumor cells in vivo with genes of pathogenic antigens from Mycobacterium tuberculosis (TB). This induces presentation of the TB antigen on tumor cell surfaces, which can be recognized by antigen presenting cells (APCs) as a “danger signal” to stimulate antitumor immune response. This strategy is also expected to amplify the immune response against tumor-associated antigens, and block immune escape of the tumor. DNA/PEI/chondroitin sulfate ternary complex is a highly effective non-viral gene vector system for in vivo transfection. A therapeutic complex was prepared using a plasmid encoding the TB antigen, early secretory antigenic target-6 (ESAT-6). This was injected intratumorally into syngeneic tumor-bearing mice, and induced significant tumor growth suppression comparable to or higher than similar complexes expressing cytokines such as interleukin-2 (IL-2) and interleukin-12 (IL-12). Co-transfection of the cytokine-genes and the ESAT-6-gene enhanced the antitumor efficacy of either treatment alone. In addition, complete tumor regression was achieved with the combination of ESAT-6 and IL-2 genes.
Highlights
As a safe alternative to viral gene carriers, we have developed a highly effective in vivo gene transfection system, which consists of small plasmid complex particles with negative surface charge [1,2]
DNA complex particles were made from plasmids encoding the early secretory antigenic target-6 (ESAT-6) gene, and the antitumor therapeutic efficacy of the pathogenic antigen transfected into syngeneic tumor-bearing mice was explored
The mechanism of immune stimulation by ESAT-6 is under investigation, together with other pathogenic antigens. This antitumor strategy could theoretically be effective in several different types of tumors, and is expected to open up a new way to overcome the current obstacles in cancer immunotherapy, including T cell tolerance against tumor antigens to evoke effective antitumor immune response
Summary
As a safe alternative to viral gene carriers, we have developed a highly effective in vivo gene transfection system, which consists of small plasmid complex particles with negative surface charge [1,2]. Apparent tumor regression was observed, but a complete response was not achieved In those animals with established primary tumors, the tumor often escapes from immune surveillance, and transfection of cytokine genes alone was not sufficient to evoke an effective antitumor immune response. We speculated that similar to virus infection, transfection of tumor cells with plasmids harboring virus- or bacteria-specific antigenic protein genes could induce pathogenic antigen presentation in the tumors. This strategy avoids the risks associated with using actual infectious organisms. DNA complex particles were made from plasmids encoding the ESAT-6 gene, and the antitumor therapeutic efficacy of the pathogenic antigen transfected into syngeneic tumor-bearing mice was explored.
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