Description

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.