DoriVac: Boosting Antigen-specific Immune Responses with DNA Origami-Based Vaccines

The Problem

Therapeutic personalized cancer vaccine technologies have made tremendous strides in recent years. Such vaccines typically present two types of molecules (ligands) to so-called antigen-presenting cells (APCs): tumor antigens, which are protein fragments derived from actual tumor cells, and adjuvants, which stimulate pattern-recognition receptors expressed by APCs. While the antigen ligands enable APCs to activate the immune system against a tumor and adjuvant ligands enhance APCs’ immune-stimulating activity, only when delivered together do they orchestrate a broad and effective tumor-specific immune response. It is believed that the spacing of ligands at the nanoscale on the surfaces of vaccines could serve as a major determinant of their efficacy in targeting immune-stimulating receptors on the surface of APCs, but so far no technology precisely addresses ligand arrangements in order to define optimal configurations for enhanced immunotherapies.

Our Solution

DoriVac is a DNA origami platform that enables the precise spacing and geometrical arrangement of adjuvant and antigen ligands on nanostructures for their exploration in vitro immune cell culture and in vivo tumor models. The best-performing configurations can be further investigated alone and in combination with other advanced cancer immunotherapies. Wyss researchers have demonstrated that the DoriVac platform allows precise arrangements of CpG oligonucleotide molecules, a model immune adjuvant mimicking bacterial and viral DNA, with highly reproducible patterns at the nanoscale. In vitro studies revealed a configuration of adjuvant ligands that maximized cross-presentation of antigens by APCs, and subsequent activation of CD4+ T helper and CD8+ T effector cells against tumor cells. In mouse models, the same configuration resulted in the strongest tumor-inhibiting responses, also involving the activation of natural killer cells and synergizing with a clinical stage “checkpoint” inhibitor for an overall improved immunotherapy outcome. The DoriVac platform thus presents a powerful technology to identify superior immune adjuvant and tumor antigen configurations as the basis for enhanced personalized cancer immunotherapies. Its core features can also be harnessed to develop more effective vaccines against infectious pathogens.

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Product Journey

The DoriVac platform was developed in the team of Wyss Core Faculty member William Shih, Ph.D., and co-initiated by Ju Hee Ryu, Ph.D. at the Korea Institute of Science and Technology. In 2021, DoriVac was selected as a Wyss Institute Validation Project based on its potential as an advanced vaccine platform for facilitating the development of new and improvement of existing immunotherapies. Alnylam Therapeutics, in its 2022 Alnylam BioVenture Challenge, awarded the DoriVac team the top prize “for their concept of creating breakthrough DNA origami-based immunotherapies to tackle cancer and infectious diseases.”

The DoriVac project by Shih and his team at the Wyss Institute and Dana-Farber Cancer Institute (DFCI) is also part of a multipronged approach taken by the NIH-funded “Immuno-engineering to Improve Immunotherapy (i3)” Center at Harvard University. Coordinated by the Wyss Institute, and including leading cancer immunologists and immune-engineers also from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), DFCI, and Harvard’s Department of Stem Cell and Regenerative Biology, the i3 Center is developing new biomaterials-based approaches to enable anti-cancer immunotherapies for therapy-resistant cancers.