1156 Small circular RNA vaccines for combination cancer immunotherapy

Background

mRNA vaccines have shown strong prophylactic efficacy against viral infections, and hold great potential for the immunotherapy for preexisiting diseases such as many types of cancer. However, current mRNA vaccines still have limitations of suboptimal biostability and thermostability, the resulting short duration of antigen production, and hence suboptimal antitumor immune responses and therapeutic efficacy.

Methods

We have developed highly stable small circular RNA vaccines that durably expressed customized antigens such as tumor neoantigens, tumor-associated antigens, or oncoviral antigens, and consequently elicited potent and long-lasting antitumor T cell responses for the immunotherapy of multiple types of tumors in combination with immune checkpoint inhibitors.

Results

Here we show that antigen-encoding small circular RNAs (circRNAs) loaded in lipid nanoparticles can elicit potent and durable T-cell responses for tumour combination immunotherapy in mice (figure 1). The small-circRNA vaccines are highly stable, and show low levels of activation of protein kinase R as well as low cytotoxicity, allowing for long-lasting antigen translation (longer than 1 week in cells). Relative to large protein-encoding circRNAs, unmodified mRNAs, and modified mRNAs, small-circRNA vaccines elicited up to 10-fold antigen-specific T cells in mice, and accounted for 30%–75% of the total peripheral CD8⁺ T cells over 6 months. Small-circRNA vaccines encoding viral antigens, oncoviral antigens, and tumour-associated antigens and neoantigens of major histocompatibility complex I or II also elicited substantial CD8⁺ and CD4⁺ T-cell responses, respectively, in young adult mice and in immunosenescent aged mice. Combined with immune checkpoint inhibition, monovalent and multivalent circRNA vaccines reduced tumour immunosuppression, and increased the complete regression rates of poorly immunogenic murine tumours, including Braf^V600E melanoma that resists dual immune checkpoint blockade (figure 2).

Conclusions

Small circular RNA vaccines thus hold the potential to advance the development of therapeutic vaccines and maximize the therapeutic potential of immune checkpoint blockade for many types of cancers.