A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce...

Area of Science:

• Immunology
• Oncology
• Vaccine Development

Background:

• Tumor-associated antigens are key targets for cancer immunotherapy.
• Germline antigens like WT1 (Wilms' tumor gene 1) are overexpressed in cancers but tolerated by the immune system.
• Existing WT1 vaccines struggle with low in vivo potency due to WT1's self-antigen nature.

Purpose of the Study:

• To develop a novel synthetic micro-consensus (SynCon) DNA vaccine to overcome tolerance to WT1.
• To enhance vaccine immune potency against germline tumor antigens.
• To evaluate the efficacy of SynCon WT1 vaccines in breaking tolerance and eliciting anti-tumor immunity.

Main Methods:

• Developed novel SynCon DNA vaccine constructs targeting WT1.
• Administered SynCon WT1 vaccines to non-human primates (NHPs) and mice.
• Assessed immune responses, including T-cell activation (IFN-γ, CD107a, TNF-α) and antibody production.
• Evaluated therapeutic efficacy in preclinical tumor models using electroporation (EP) delivery.

Main Results:

• SynCon WT1 vaccines induced neo-antigen-like responses superior to native WT1 immunogens.
• NHPs showed immune responses against native rhesus WT1 peptides post-vaccination.
• Mice exhibited robust CD4 and CD8 T-cell responses to both native and consensus WT1 peptides.
• Vaccine-induced antibodies recognized native WT1 in vitro, and vaccination slowed tumor growth in vivo.

Conclusions:

• Synthetic consensus DNA vaccines represent a novel strategy for breaking tolerance to germline tumor antigens like WT1.
• SynCon WT1 vaccines demonstrate significant potential for enhancing anti-tumor T-cell immunity and therapeutic efficacy.
• This approach warrants further investigation for developing effective cancer immunotherapies targeting broadly expressed germline antigens.