Cancer vaccine using SynCon® technology enhances neo-antigen-like T cell response to break tolerance and induce anti-tumor immunity
Jing Chen1, Jian Yan1, Jewell N. Walters1, Bernadette Ferraro1, Elizabeth K. Duperret2, Kimberly A Kraynyak1, Matthew P. Morrow1, Amir S. Khan1, David B. Weiner2, and Laurent M. Humeau1
1Inovio Pharmaceuticals Inc, 660 W. Germantown Pike, Plymouth Meeting, PA 19462, USA; 2 Wistar Institute, 3601 Spruce Street, Room 630, Philadelphia, PA 19104, USA
Cancer vaccines are often poorly immunogenic because of the immune tolerance to the targeted self-antigens. Studies have shown that alteration in peptide sequences can alter antigen presentation and T cell receptor recognition, leading to increased immunogenicity. Here, we proposed a novel multi-phase DNA vaccine design strategy (SynCon® Technology) to design neo-antigen like cancer immunogens. By introducing subtle amino acid changes into native cancer antigens, we hypothesized that SynCon® antigen should exhibit stronger ability to break tolerance.
As a proof of concept, we first designed a WT1 vaccine using SynCon® Technology (SynCon® WT1). SynCon® WT1 shares about 95% sequence identity with human and rhesus macaque native WT1, while 92% sequence identity with mouse native WT1. In a murine model, we demonstrated that vaccination with SynCon® WT1 was able to break tolerance and induced robust cellular immune responses against mouse native WT1 peptides(~200 SFU/106 splenocytes), while there were little to no cellular response detected in mice immunized with native mouse WT1. Importantly, SynCon® WT1 could also break self-tolerance in rhesus macaque. SynCon®WT1 vaccination also delayed tumor growth in a mice leukemia therapeutic tumor model. Preclinical studies on multiple self-antigens including hTERT, PSMA and PSA, which were designed using the same strategy, showed that these SynCon® antigens could also break tolerance and induce robust cellular immune responses.
Taken together, we demonstrated that SynCon® technology can be used to design novel cancer vaccines with neo-antigen like properties. These data warrant further investigation of SynCon® immunogens in clinical trials.
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