Non-small cell lung cancer (NSCLC) treatment was strongly improved by immune checkpoint inhibitors (ICI). However, < 30% of patients demonstrate long-term benefit. We hypothesize that therapeutic mRNA vaccination, coupled with co-targeting of antigen-presenting cell (APC) immunosuppression, will sharply increase the spectrum of patients who could benefit from ICI. Following COVID19 paradigm shift in vaccines, in which mRNA came to the forefront, we predict that this flexible technology will revolutionize personalized cancer care. Based on our complementary expertise, we aim to obtain PoC for a novel NSCLC mRNA vaccine, based on an innovative mRNA + siRNA combination therapy to modulate antigen presenting cells (APC) toward restructuration of tumor microenvironment (TME).
WP1 will establish mRNA/siRNA cargo, allowing model tumor-associated antigen (TAA) expression in APC + inhibition of ATP degradation by siRNA knockdown of ENTPD1/CD39. Alternatively, siRNA-mediated DICER knockdown to avoid immunosuppressive polarization of APC will be evaluated. In addition, we will design novel poly(beta aminoester) polymers, selectively targeting TME APC, and formulate nanoparticles (NPs) to be administered using minimal invasive routes. WP2 will finely characterize each monotherapy and combinations. WP3 will test the safety and efficacy of NPs using tumor-naïve mice and TME in vitro models. WP4 will evaluate the most effective NPs in ICI refractory autochthonous NSCLC mouse models to determine its ability to increase ICI responsiveness. WP5 aims at personalizing nanotherapeutics by developing a method to allow TAA prediction from genome sequencing of (liquid) biopsies. WP6 will initiate technology transfer, prior to presenting clinical trial protocols to regulatory authorities.
Through TumorOUT, we expect to revolutionize NSCLC treatment, and impact patient quality of life and costs to healthcare systems by the generation of a next generation personalized medicine.