mRNA-based dendritic cell vaccines

Abstract

Cancer immunotherapy has been proposed as a powerful treatment modality. Active immunotherapy aspires to stimulate the patient’s immune system, particularly T cells. These cells can recognize and kill cancer cells and can form an immunological memory. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system. They take up and process antigens to present them to T cells. Consequently, DCs have been investigated as a means to stimulate cancer-specific T-cell responses. An efficient strategy to program DCs is the use of mRNA, a well-defined and safe molecule that can be easily generated at high purity. Importantly, vaccines consisting of mRNA-modified DCs showed promising results in clinical trials. Therefore, we will introduce cancer immunotherapy and DCs and give a detailed overview on the application of mRNA to generate cancer-fighting DC vaccines.

Keywords:

• cancer
• cytotoxic T cell
• dendritic cell
• mRNA
• tumor antigen

Key issues

• Cancer immunotherapy aspires to harness the patients’ immune system in the fight against cancer.

• Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system capable of stimulating novel or enhance existing anti-tumor immune responses. To that end, DCs need to present antigenic peptides and provide co-stimulatory signals, such as those provided by CD80/CD86 and CD70, or cytokines like IL-12p70.

• mRNA is safe, inexpensive to produce and well-defined chemically, which facilitates quality control and ensures reproducible manufacturing and activity. Importantly, mRNA encoding tumor antigens and immune modulating proteins can be efficiently delivered to DCs in order to deliver an anti-tumor message.

• Clinical trials using mRNA-modified DCs show promising results, as objective response rates are frequently reported.

• Short-term future perspectives include the combination of DC vaccination with immune checkpoint blockade.

• Long-term future perspectives include the shift from ex vivo modification of DCs to in vivo modification of DCs. To that end, it will be crucial to optimize formulations in which the mRNA is encapsulated in nanoparticles that when desired can be targeted to specific DC subsets.