UCLA researchers in the Department of Chemistry and Biochemistry have developed a novel method for delivering RNA to induce an immune response to cancer cells.
BACKGROUND: Cancer therapy continues to remain a challenge despite improvements in detection and clinically available therapies. Recently, improvements to this field have been mainly in the field of immunotherapy, which has been able to develop personalized therapies for each patient. Even though there are many advantages, many of these personalized therapeutics, such as CAR-T therapy, are cumbersome and costly, thus preventing widespread use. A more cost-efficient alternative are cancer vaccines that stimulate a person’s immune system to generate killer T-Cells that target and kill cancer cells. Valued at $4.2 Billion in 2014, cancer vaccines have the potential to take up a large portion of the cancer therapeutic market. Despite significant advances, cancer vaccines have had limited success in generating a strong immune response able to eradicate tumors. Stronger T-Cell activation will elevate cancer vaccines to the forefront of personalized cancer therapies providing a cost-effective, faster and more adaptable solution.
INNOVATION: UCLA researchers led by Dr. William Gelbart have developed virus-like particles containing self-amplifying (sa) RNA for use as a powerful cancer vaccine. In collaboration with Boehringer-Ingelheim they were able to: demonstrate that activation of dendritic cells (DCs) is greatly enhanced by packaging the saRNA in virus-like particles (VLPs) functionalized with DC-targeting ligand; and to use these VLPs to elicit a killer T-cell response to the sa-antigen in mouse models. Combination of this vaccination strategy with co-delivery of VLPs containing saRNA encoding a constitutively-active protein (“STING”) generates significant interferon production by short-circuiting the STING pathway. This is the first cancer vaccine in which the RNA antigen sequence is self-amplifying and in vitro reconstituted in a perfectly monodisperse, RNase-resistant, spherical protein shell ensuring selective yet high delivery and expression rates. Uptake of these VLPs by DCs can be further enhanced by conjugation with immunogenic and/or targeting ligands, and their T-cell response boosted by co-delivery of VLPs containing STING in saRNA form. Advancement and further optimization of this innovation brings significant opportunities for the development of a wide range of cancer therapeutics and – due to its unique delivery system – many alternative applications such as viral vaccines and delivery of other therapeutic targets.
POTENTIAL APPLICATIONS:
• Cancer Vaccines
• Virus Vaccines
• Research Tools
ADVANTAGES:
- Efficiently taken up by dendritic cells, because of their specific targeting and protection in VLPs
- Self-Replicating RNA encoding the vaccine antigen strongly enhances immune response
- Results in a large number of antigen-sensitive killer T-Cells that can be boosted further by short-circuiting of the STING interferon-production pathway
DEVELOPMENT-TO-DATE: UCLA researchers have tested this method both in vitro and in vivo and shown that activation of dendritic cells is strongly enhanced by packaging of the RNA antigen in self-amplifying form. Mouse models contained antigen-sensitive killer T Cells after treatment, in comparison to untreated mice. Separately, constitutively-active STING protein in self-amplifying RNA has been shown to generate significant levels of interferon production, suggesting that it can be used effectively as an adjuvant for boosting immune responses to T-cell vaccines.
Related Papers (from the inventors only): Biddlecome A, Habte HH, McGrath KM, Sambanthamoorthy S, Wurm M, Sykora MM, et al. (2019) Delivery of self-amplifying RNA vaccines in in vitro reconstituted virus-like particles. PLoS ONE 14(6): e0215031. https://doi.org/10.1371/journal.pone.0215031
Keywords: Immunotherapy, Cancer, Cancer Vaccine, Antigen, Killer T Cells, Self-amplifying RNA, Virus-like Particles, Dendritic Cells, STING pathway, Interferon Production