In March 2024 researchers at Wyss Institute announced the publication of research that indicates the possibility that DNA origami could serve as a platform for “controlling adjuvant spacing and co-delivering antigens in vaccines”. Their platform, DoriVac, enables the “precise spacing and geometrical arrangement of molecules” on nanoparticles to produce “highly effective and personalised immunotherapies”. Developed in collaboration with Dana-Farber Cancer Institute, Harvard Medical School, and Korea Institute of Science and Technology, the platform is intended to overcome several “problems” associated with cancer immunotherapy.
Identifying a need
Wyss Institute comments that “serious diseases” such as cancer and autoimmune conditions demand “multiple drugs”. However, combining drugs is “challenging” for several reasons, including toxicity. This occurs when the side effects of multiple drugs “compound each other” to produce “much greater patient suffering”. Furthermore, drug combinations can lead to “increased costs for patients and insurers”.
The team specifically address the problem in personalised immunotherapy, where both tumour antigens and adjuvants need to be presented to antigen-presenting cells (APCs).
“It is yet unknown how these molecules might interact with each other when co-delivered, or how to optimise the process and the dosages to produce the strongest anti-cancer response.”
Enter DoriVac
DoriVac is a DNA origami platform that has identified “molecular patterns” to produce “superior immune responses while minimising” the drugs required. This reduces costs and off-target side effects.
“DoriVac also has numerous advantages over other nanoparticle platforms, including targeting to specific compartments within cells and co-delivering multiple types of molecules to desired targets at the lowest possible doses.”
The “core component” of DoriVac is a “self-assembling square block-shaped nanostructure”. On one face of the block, defined numbers of adjuvant molecules can be attached in “highly tunable, nanoprecise patterns”, with the opposite face binding tumour antigens.
In study
The study, which is not open access, identified that molecules of the CpG adjuvant spaced exactly 3.5 nanometres apart resulted in the “most beneficial stimulation of APCs” that induced a “highly desirable profile of T cells”. The adjuvant is a synthetic strand of DNA comprising repeated CpG nucleotide motifs that “mimic the genetic material from immune cell-invading bacterial and viral pathogens”. It binds to a “danger receptor” called TLR9, which induces an inflammatory response that “works in concert” with the antigen-induced response.
First author Dr Yang (Claire) Zeng commented that previous work highlighted the importance to TLR9 receptors dimerising and aggregating into multimeric complexes binding to multiple CpG molecules.
“The nanoscale distances between the CpG-binding domains in effective TLR9 assemblies revealed by structural analysis fell right into the range of what we hypothesised we could mirror with DNA origami structures presenting precisely spaced CpG molecules.”
Dr Zeng and the team were “excited” to find that the DoriVac vaccine “preferentially induced an immune activation state that supports anti-tumour immunity”, something that “researchers generally want to see in a good vaccine”.
As well as the spacing, the numbers of CpG molecules in DoriVac vaccines made a difference, with 18 providing the “best APC activation”. The key finding is that the observations “translated to in vivo mouse tumour models”. The vaccines, injected under the skin of mice prophylactically, accumulated in the closest lymph nodes to stimulate DCs. A vaccine loaded with a melanoma antigen prevented the growth of aggressive melanoma cells upon challenge.
Although the control animals “succumbed” to the cancer by day 42 of the experiment, DoriVac-protected animals were alive, and displayed inhibited tumour growth in mice that already had formed melanoma tumours. The team also investigated if DoriVac vaccines could boost immune responses produced by neoantigens in melanoma tumours. A DoriVac vaccine with four neoantigens enabled them to “significantly suppress growth of the tumour in mice that produced the neoantigens”.
The last test was if DoriVac could “synergise with immune checkpoint therapy”. The combination resulted in the “total regression” of melanoma tumours, and prevented recurrence when the animals were exposed to the same tumour cells four months later. Dr Zeng believes that “DoriVac’s value for determining a sweet spot in adjuvant delivery” and “enhancing the delivery and effects of coupled antigens” could “pave the way to more effective clinical cancer vaccines”.
Technology for the future
Dr William Shih, who led the team at the Wyss Institute with Dr Zeng, suggests that the DNA origami technology “merges different nanotechnological capabilities that we have developed over the years with an ever-deepening knowledge about cancer-suppressing immune processes”.
“We envision that in the future, antigens identified in patients with different types of tumours could be quickly loaded onto prefabricated, adjuvant-containing DNA origami to enable highly effective personalised cancer vaccines that can be paired with FDA-approved checkpoint inhibitors in combination therapies.”
Dr Donald Ingber, Founding Director of the Wyss Institute, states that the platform is “our first example of how our pursuit of what we call Molecular Robotics – synthetic bioinspired molecules that have programmable shape and function – can lead to entirely new and powerful therapeutics”.
“This technology opens an entirely new path for the development of designed vaccines with properties tailored to meet specific clinical challenges. We hope to see its rapid translation into the clinic.”
For more on innovative technology to revolutionise cancer immunotherapy do get your tickets to the Congress in April or subscribe to our newsletters here!
