A synthetic RNA delivery platform for universal ex vivo modification of natural killer cells
This project will focus on the generation of new tools to treat oncological patients. A new strategic alliance with Glycostem will be established to generate engineered natural killer (NK) cells that could be used for cell-therapy approaches in several types of cancers.
Every year there are over 14 million new global cancer cases and this number is expected to grow to 23.6 million by 2030. We know that hematological cancers are around 6.5% (917,907 cancers) of all cancer types. Cancer immunotherapy has emerged as the new growth frontier for the pharmaceutical companies involved in the clinical research and development of cancer drugs and therapeutics. Here the aim is to develop new cell therapies similar to the technologies that have yielded the highest number of ongoing clinical trials in the field of immuno-oncology.
The efficacy of NK cell-mediated immunotherapy can be enhanced by immune stimulants such as cytokines and antibodies, and adoptive transfer of activated NK cells expanded ex vivo. For most cell-engineering modifications delivery of genetic material in these cells is required. The currently available techniques for genetic modification of immune cells for adoptive cell therapy have major drawbacks regarding safety and efficiency. In this proposal, there will be capitalised on the extensive experience in making synthetic mRNA delivery systems based on biodegradable polymers. Proposed is the development of a scalable and universal delivery platform for mRNA-based genetic modification of immune cells, with the focus on NK cells.
This project will lead to the generation of new delivery systems that will be cheap to manufacture in a scalable and reproducible way, efficient in transfecting NK cells, fully biodegradable, small enough to enable sterile filtration and with a good toxicity profile towards NK or feeder cells.
Cellular immunotherapy is conquering the field of immuno-oncology (IO). Genetically engineered T cells have been brought to the market by the biggest pharmaceutical companies. However, few drawbacks in manufacturing (high costs) and clinical application (toxicity) are favoring the development of allogeneic (“off-the-shelf") products like natural killer (NK) cells. Unlike T cells, NK cells have the advantage that they do not attack healthy self-tissue nor do they have the risk of inducing a cytokine storm. The efficacy of NK cell-mediated immunotherapy can be enhanced by immune stimulants such as cytokines and antibodies, and adoptive transfer of activated NK cells expanded ex vivo. In addition, NK cells can arm themselves with chimeric antigen receptors (CARs), which may greatly enhance their anti-tumor activity. For most of these modifications delivery of genetic material in these cells is required. The currently available techniques for genetic modification of immune cells for adoptive cell therapy have major drawbacks. Viral vectors, although efficient in transduction, are expensive to make under GMP and at large quantities. Further, their potential safety issues are major impediments. Electroporation on the other hand can be effectively scaled up but toxicity issues remain a problem. In this proposal, we will capitalize on our extensive experience in making synthetic mRNA delivery systems based on biodegradable polymers. In this project we developed a scalable and universal delivery platform for mRNA-based genetic modification of immune cell by using an optimized lipid-nanoparticle (LNP) formulation. This LNPs proved to outperform electroporation, lipofectamine and other polymer-based delivery systems in transfecting NK cells. Such an enabling platform will have widespread use in adoptive cell therapies that go far beyond the examples that will be addressed in this proposal.
