Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy

Abstract

The induction of a strong cytotoxic T cell response is an important prerequisite for successful immunotherapy against many viral diseases and tumors. Nucleotide vaccines, including mRNA vaccines with their intracellular antigen synthesis, have been shown to be potent activators of a cytotoxic immune response. The intracellular delivery of mRNA vaccines to the cytosol of antigen presenting immune cells is still not sufficiently well understood. Here, we report on the development of a lipid nanoparticle formulation for the delivery of mRNA vaccines to induce a cytotoxic CD 8 T cell response. We show transfection of dendritic cells, macrophages, and neutrophils. The efficacy of the vaccine was tested in an aggressive B16F10 melanoma model. We found a strong CD 8 T cell activation after a single immunization. Treatment of B16F10 melanoma tumors with lipid nanoparticles containing mRNA coding for the tumor-associated antigens gp100 and TRP2 resulted in tumor shrinkage and extended the overall survival of the treated mice. The immune response can be further increased by the incorporation of the adjuvant LPS. In conclusion, the lipid nanoparticle formulation presented here is a promising vector for mRNA vaccine delivery, one that is capable of inducing a strong cytotoxic T cell response. Further optimization, including the incorporation of different adjuvants, will likely enhance the potency of the vaccine.

mRNA vaccines — a new era in vaccinology

“…In the same study, coadministration of mRNA encoding granulocyte–macrophage colony-stimulating factor (GM-CSF) improved OVA-specific cytolytic responses. Another report showed that subcutaneous delivery of LNP-formulated mRNA encoding two melanoma-associated antigens delayed tumour growth in mice, and co-delivery of lipopolysaccharide (LPS) in LNPs increased both CTL and antitumour activity 153 . In general, mRNA cancer vaccines have proved immunogenic in humans, but further refinement of vaccination methods, as informed by basic immunological research, will likely be necessary to achieve greater clinical benefits.…”

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…This idea has increased the efficacy of candidate immunotherapies involving whole tumor cell lysates through improved targeting to DCs [65,67]. Biomaterials have also been used to increase the efficacy of checkpoint blockade therapies by better selective targeting to specific cell types, decreasing systemic side effects [68,69]. Only now are some of these ideas filtering into clinical trials [70], highlighting the need to use more rigorous preclinical models in testing biomaterials and to push toward clinical studies.…”

Immunomodulating Nanomedicine for Cancer Therapy

“…10 Similarly, lipid nanoparticles assembled with specified compositions were recently shown to protect RNA sequences from extracellular ribonuclease degradation and promote their efficient uptake by professional antigen-presenting cells to express tailor-designed antigenic peptides in vivo. 11 Using RNA sequences that encode viral or mutant neo-antigens, these nanoparticle constructs induce strong antitumor effector and memory T-cell responses through potent IFNα activation (Figure 1a). 12 Remarkably, early clinical data from the first three melanoma patients treated with these lipid nanoparticle–RNA constructs showed strong IFNα and antigen-specific antitumor responses, 12 thus offering significant hope that such a system can be readily translated to the clinic.…”