Enhancing T-cell response in cancer immunotherapy using nanoparticles

Immunotherapy has been used in oncology in order to awaken the immune system of the patient against cancer. Within this promising field is emerging the use of therapeutic cancer vaccines, using tumor specific antigens to stimulate dendritic cells (DCs) ex vivo, followed by administration to patients to induce a cancer-specific immune response. The ex vivo approach is coming with some disadvantages, for example the waste of time and biological material deriving from the procedure. Furthermore, the direct injection in the patient of tumor antigens that could be uptaken by dendritic cells and give rise to an immune response has not shown clinical relevance. It has been demonstrated that delivering these antigens encapsulated in nanoparticles rather than in their free format, can improve their immunogenicity and uptake by DCs, but improvements are still needed in order to achieve a proper clinical relevance. The aim of this project is to develop such platforms to enhance nanoparticles uptake by DCs and obtain a tumor specific T-cell response. A great improvement suggested in this Project is the attempt to use a higher immunogenic oxidized tumor lysate instead of single specific antigens or non modified tumor lysate. For this purpose, the first part of the Project is focusing on the production of biocompatible, non-toxic PEG-PLGA nanoparticles for the encapsulation and delivery of oxidized tumor lysate. Studies regarding chemical and physical features of nanoparticles together with any toxicity towards DCs will be undertaken. Preliminary studies will consist of estimating the uptake profile, in vitro response and evaluation of the best dose to deliver. The second part will focus on the possibility of using internal stimuli responsive materials in the production of nanoparticles, to increase cross-presentation by DCs. These internal stimuli are classically depending on the intracellular environment, such as pH and reactive oxygen species (ROS), and could enhance endosomal escape, cross-presentation and offer a strategy of controlled release. Another approach aimed at increasing cross-presentation and immune response involves the use of bacteria, and will be addressed in the third part of the Project. In this case, bacteria are used as a dock over which it will be possible to bind the nanoparticles and facilitate uptake by DCs, immunostimulation and cross-presentation to T-cells. Finally, the last part will focus on the co-delivery of tumor lysate loaded nanoparticles and immunostimulating ones. The latter will combine FDA approved drugs Interleukin-2, IL-2 (Proleukin®), and Ipilimumab (Yervoy®) or Nivolumab (Opdivo®) delivered by a responsive particle. The monoclonal antibodies on the surface of the particle will work both as immunecheckpoint inhibitors and T-cell specific binders, while IL-2 will be released following an external stimulus to increase T-cell proliferation in a temporally and spatially controlled manner.