Next-Generation of Smart Targeted Cancer Nanovaccines

KNAW: Academy funding for Nanotechnology project

LUMC researcher Dr. Luis Cruz (Radiology) received an Academy China Exchange Programme scholarship. This project facilitates scientific collaboration and stimulates exchanges between China and the Netherlands by funding joint research projects. In collaboration with the research group of Prof. Dezhen Shen (Changchun Institute of Optics, China), Dr. Luis Cruz will execute a project for nanotechnology in immunotherapy.

Next-Generation of Smart Targeted Cancer Nanovaccines

All modalities of cancer therapies have improved in the last decade, however, we are still far from considering cancer as a beatable disease. Often tumor cells generate resistance to different kinds of chemotherapy treatments driving to cancer dissemination and metastasis. For this reason, it is essential to develop new therapeutic strategies for attacking the disease from different fronts. In this sense, the importance of the immune system in the host response against cancer has been studied for many years. However, cancer vaccines have proved to be only modestly effective, because some limitations in cancer patients (e.g. immunosuppression in advanced cancer patients) preclude the success of single immunotherapy as alternative to the classical treatments. Therefore, it is necessary the development of new tumor vaccines based to the light of new knowledge about cancer immunology and immunomodulation.

In a general sense, vaccination has proven to be among the most efficient forms of immunotherapy. The primary goal of cancer vaccination is to generate robust and specific T cell responses with the capacity to inhibit tumor growth in cancer patients, in which there is a poor tumor-specific natural immunity. To date, many of the cancer vaccines are performed by means of dendritic cells (DCs) - the main antigen presenting cells (APC) – which are loaded with tumor-associated antigens (TAA) and activated with immune-stimulatory factors (adjuvants). DC-based tumor immunotherapeutic strategies involve ex vivo loading of DCs with subsequent re-injection back into the patient to boost their in vivo T cell activation. Another strategy is, after isolation of lymphocytes from cancer patients, to expand tumor antigen-specific T cells ex vivo and adoptively transferred back into the patient. However, both techniques require the use of autologous cells, and are therefore hampered by the multiple laborious steps that vaccine preparations require, among them the use of good manufacturing practices (GMP)-regulations and donor variability. Alternatively, instead of adoptive transfer of ex vivo manipulated autologous cells, nanovaccines have been designed for in vivo induction and activation of tumor-specific Cytotoxic T Lymphocytes (CTLs). 

The aim of this project is to construct a new generation of nanoparticles (NPs) as antigen delivery system that is capable to target DCs and efficiently evoke a robust tumor-antigen specific T cell response. Biodegradable polymers are utilized for sustained delivery of bioactive molecules. They release their contents within days, weeks or even months, depending on particle composition and the solvent. These nanoparticles are generally coated with polyethylene glycol (PEG), which builds a sterically repulsive shield that protects the particles from non-specific interactions with cells and thereby minimizes rapid particle clearance. Additionally, PEG chains sterically stabilize the NPs against opsonization and subsequent phagocytosis. Nanovaccine based antigen delivery system which will carry a polypeptide antigen as well as adjuvants and αGalCer, will be coated with a PEG-lipid layer and decorated with targeting antibodies, to the same APC. In this research we study combined targeting to DCs with antibodies to CD40, DEC205 and a C-type lectin receptor (CLR). After uptake by DCs, the nanoparticles should have a sustained slow release of antigens. Tumor antigen peptide (TAA) will be used as antigen and Pam3Csk4 (TLR2 ligand) and Poly(I:C) (TLR3 ligand) will be loaded as adjuvants. The nanovaccine should prove to evoke a robust tumor-antigen specific T cell response in vitro as well as in vivo. Furthermore, side effects, optimal dosing regimen, and pharmacokinetic and pharmacodynamics, need to be assessed to pave the way toward first in human trials.