Smart design nanoParticles to Activate immune Responses against Cancer (SPARC)

The prospect of stimulating immune responses to specifically kill cancer cells, instigated research into cancer vaccines. The positive results on systemic delivery of mRNA packaged in lipid nanoparticles (LNPs) in patients are very exciting, since LNPs avoid the complex logistics associated with ex vivo strategies. We recently developed LNPs containing tumor antigen mRNA and the adjuvant α−galactosylceramide (α-GC-LNPs). These are able to induce a high tumor influx of cytotoxic T lymphocytes (CTLs) and invariant natural killer T (iNKT) cells, thereby tackling cancer from two angles. However, recently we discovered that these cells receive inhibitory signals via the PD-1 receptor, which binds PD-L1 expressed on antigen-presenting cells (APCs) and cancer cells resulting in iNKT-cell anergy and CTL-paralysis. Therefore, we aim to boost the efficiency of the developed α-GC-LNPs by developing a dual treatment regimen, based on the spatio-temporal expression PD-L1 after vaccination, in which α-GC-LNPs are paired with PD-1/PD-L1 inhibition at these two fronts. We will study the treatment regimen in vivo, evaluating its effect on APCs, CTLs, iNKT cells, and its ability to mediate tumor regression. As most experiments are performed in laboratory animals, and therefore designed to accrue to the principle of reduction, we included the development of a novel non-parametric statistical toolbox with hypothesis tests suitable for small datasets with high power.