Developing new anti-bacterial vaccines based on synthetic polysaccharides

Erasmus Plus

The planned mobility project will further strengthen and institutionalize the already existing collaboration between Leiden University Medical Center (LUMC), Havana University, and the Havana Medical Sciences University in Cuba. This mobility project with Cuba is in line with the general intention and strategy of Leiden University to create a more international student, to strengthen the international character of the University, to internationalize the learning experience for all students, and to extend our collaborative networks to other countries and regions. More specifically, the Leiden University Medical Center has chosen several countries to cooperate and Cuba is one of the designated countries. Cuba was selected due to its high level of preventive care and vaccine research (despite the impact of international sanctions on medicine and medical supplies, Cuban health outcomes are comparable to those of developed countries [2010, Science, 328, 572-573]). 

The main reason for starting a mobility project in the framework of Erasmus+ KA1 is to make the mobility between the Netherlands and Cuba two-sided. The knowledge and skills available in both countries are of an equal level, but mobility is currently limited to staff and students going from Leiden to Havana, but not from Havana to Leiden. The project would greatly benefit from a more equal participation from both sides. Unfortunately, there are no funds available in Cuba for either the staff or student mobility to the Netherlands. Erasmus+ funding would enable such a mobility opportunity.

Within the project, the Cuban partners will design and develop new tools that are important for anti-cancer and vaccination strategies. These tools, developed by Cuban students, will be tested and optimized with in vitro/in vivo experiments at the Leiden University exploiting the state-of-the-art facilities, equipment and knowledge that is available at the LUMC. Therefore, the planned mobility project will be a unique experience for Cuban students. At the same time, the Cuban preventive health care system can also serve as an example for the Netherlands in its efforts to keep health care affordable.

Students from Havana have an excellent level in chemistry/biology and immunology. In Leiden they will be trained in immunology (LUMC) and in nanotechnology and molecular imaging applied to immunology (Leiden Institute of Chemistry and Nanomedicine and Molecular Imaging at the Radiology Department from Leiden University Medical Center). Staff members from Havana will come to Leiden for training/teaching. Staff members from here will go to Havana only for teaching.

In Cuba they are developing new anti-bacterial vaccines based on polysaccharides. Here we will study a way to optimize the vaccine-efficacy. For this type of studies the facilities and expertise from LUMC are necessary, which include the immunology lab, cell culture and flow cytometry (expensive apparatus). In addition, Leiden will also develop a nanotechnology approach based on the Cuban vaccines. To teach Cuban students all these new approaches and new areas of immunology and chemistry, staff from Leiden will go to Havana. In conclusion, we have a practical training based on new results (Cuban students here in Leiden), and a tutorial/teaching aim in Havana. The carbohydrate-vaccine field is new and the Cubans were pioneers in this field.

Preclinical Intraoperative Image-Guided Surgery via Upconversion Nanoparticle

FUND NCI – Technology Area (TA) (NWO)

Our proposal will revolve around the development of fluorescence chemistry upon an upconversion nanoparticle (UCN) platform to provide a targeted and less toxic approach towards tumour therapy. UCNs also display the unique property of emitting visible light following photoexcitation with near-infrared laser light. This results in features such as absence of autofluorescence (from biological matter) and easy separation of the emission bands from stray light and the absence of blinking effects. In addition, we will add the targeted radionuclide component as postoperative treatment after image-guided surgery. A bioorthogonal chemical reaction will be employed for the recruitment of the small radiolabeled probe to the targeting moiety. The benefit of such a reaction is that the radiotherapy would only target tumour cells. Once the technique gets implemented clinically, it would mean that the patient does not incur systemic side-effects resulting in hair loss or prolonged nausea, etc., which is often seen in more conventional treatments.

Image-Guided Surgery (IGS) and Personalised Postoperative Immunotherapy to Improving Cancer Outcome

Despite progress in all the areas of cancer treatment, both in surgery, chemotherapy, radiation therapy and immune therapies, there is still a long way to consider that we are close to defeat this plague of the advanced societies. The importance of the immune system in the host response against cancer has been studied for many years. However, treatment of cancer by single immunotherapy has been proven to be only modestly effective. The aim of this project is to address the issues of postoperative immuno-modulation after Image-Guided Surgery (IGS) by means of nanoparticles-based encapsulated libraries of different immunotherapeutic biomolecules that are needed to improve cancer outcome. 

Surgery remains an effective treatment option for many types of cancer today and it is considered curative treatment for most solid tumors. It forms part of a multidisciplinary approach used in conjunction with radiotherapy or chemotherapy. These approaches, however, have several limitations, including inability of surgical resection to affect distal metastatic disease, toxicity to healthy tissues with chemotherapy and lack of effectiveness of radiation therapy in more aggressive tumors. The observation that cancer can relapse months or years after initial surgery implies that micrometastases still resides within the body in a latent state. Nanoparticles (NPs) are new concepts of treatment that allow encapsulate many different types of molecules, as: chemotherapeutic drugs, avoiding their free circulation and unspecific toxicity. They could be targeted to specific cells (e.g. cancer cells) precluding toxicity to healthy tissues and organs. At the same time, NPs permit to be loaded with dyes to identify tumor cells in distal points of the body or with tumor antigens, acting as vaccines or immunomodulatory molecules activating the immune response. Our approach will centre on a polymeric and biodegradable nanoparticles, degraded in the cells as physiological metabolites (no toxics), which is already FDA approved, but we will make structural changes, e.g. hydrophobicity, charge, molecular weight, to manipulate its adjuvant activity then monitor in vivo immune function such as T-cell activation and tumor regression in parallel and in dual colour. NP-based encapsulated libraries of different immunotherapeutic biomolecules, e.g. checkpoint blockade with a vaccine, will provide a versatile platform for this work. This means having the multiplex capability to target, to incorporate different immune components, based on a personalised approach of using specific molecular profiles derived from each patient, whereby combination immunotherapy will be implemented to optimally recruit the hosts’ own immune system to eradicate distal metastases and to image therapeutic efficacy.

KNAW: 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.

Targeted Cartilage Regeneration: TargetCaRe

Mobility is very important for human well-being, but the worldwide burden of chronic diseases of the musculoskeletal system, in particular osteoarthritis (OA) and chronic low back pain caused by intervertebral disc disease (IVD), impair seriously this condition in many people worldwide. The cause of these pathologies is the degeneration of the cartilaginous tissue of the intervertebral disc and joint. The search for a solution to these diseases has incited considerable scientific efforts to finding regenerative treatments mainly focused in the use of growth factors and stem cells that would cure or at least slow their progression. However, none of these new techniques have achieved to the clinic as a routine treatment yet. Complicating issues are the need for high loads of active factors, adverse effects on non-involved neighbouring and distant tissues, the rapid loss of exogenously applied stem cells and the tight regulations on advanced medicinal products. 

The objective of the TargetCaRe project aims both to prevent further degradation of a damaged joint or IVD, as well as to activate the body’s own regenerative capacity to heal damaged and degenerated tissues in the joint and the IVD. This will be carried out by a consortium, consisting of world-leading scientists, and at same time will train a group of researchers skilled in a variety of innovative technologies that will enable the development of regenerative treatments that will go beyond the current state-of-art and actually make clinical application of regenerative medicine for joint and intervertebral disc diseases feasible and successful. To this end, targeting strategies tailored to both the pathology and the tissues involved will be employed. Regeneration of diseased tissues will be achieved by targeting strategies developed to ensure that the nanocarriers containing therapeutical molecules by a controlled release will get to the damaged tissue in the joint or IVD after injection, to fully exploit the body’s own capacity for regeneration by attracting local stem cells or inhibit degeneration. Targeting will be achieved by A] injection with synthetic or natural hydrogels loaded with the nanocarriers or B] coupling diseased tissue-specific antibodies and specific hyaluronic acid moieties to the nanocarriers. High tech imaging methods will be used to monitor the delivery of the nanocarriers, the distribution of the delivered compounds at the tissue level, and the effect of the therapeutic molecules on the damaged joint or IVD tissue by detecting biological markers of regeneration.

Major objectives: 1] To establish a network of scientists skilled in the use of smart nanocarriers, unique approach of targeting by disease specific molecules and application of innovative imaging tools. 2] To develop strategies exclusively targeting diseased tissues with controlled doses of bio-actives, circumventing the disadvantages of the current shotgun approaches in regenerative medicine.

Nano-vehicles as a Platform for Tracking and Immunochemotherapy of Cancer

Vidi Grant

Cancer therapy can be made more efficient by combining targeted chemotherapy delivery with immunotherapy. Nano-vehicles, such as liposomes or polymeric nanoparticles, can be used to visualize cancer cells, protect and deliver chemotherapy, and simultaneously modulate the immune system, either systemic or in situ.

One of the aims in this project is to reduce the side effects of chemotherapy by utilizing nanoparticles. One method we can employ to achieve this, is to reduce the chemotherapy dose. To make sure that the capacity of killing cancer cells is not lost, we assemble nanoparticles to deliver a low-dose of chemotherapy directly to cancer cells. By actively targeting cancer cells using specific cancer cell receptor ligands, there is less chemotherapy required which leaves most healthy cells left unaffected. As such, side effects of chemotherapy are considerably reduced whilst maintaining the effective capacity to kill cancer cells. In addition, to augment the killing capacity of chemotherapy, we are studying the most potent chemotherapy combinations as well as their capacity to induce immunogenic cancer cell death.

On the other hand, some cancer cells may develop mechanisms of resistance against chemotherapy, change their molecular make-up and metastasize to regions of the body that are difficult to reach for nanoparticles. To anticipate this response, we aim to modulate the immune system to recognize cancer cells and at the same time provide the right cues necessary to licence immune cells to kill the remaining or metastasized cancer cells. This is a very promising strategy, as immune cells can locate cancer cells at sites in the body that nanoparticles cannot reach. Additional acquired traits include immunological memory, which ensures prolonged fighting against cancer cells, and rapid reactivation of the immune system in the event any cancer cell escaped detection and resurface years later. For this purpose, we employ member ligands of the Toll-Like receptors and other powerful immune stimulants that we co-encapsulate in our nanoparticles together or separately with chemotherapy. These nanoparticles are then targeted to the tumor microenvironment or to specific subset populations of the immune system. We also study the combination of these nanoparticles combined with immune check-point blockers, cancer vaccines, or small inhibitor molecules.

Erasmus Plus

Developing new anti-bacterial vaccines based on synthetic polysaccharides, (EU) Erasmus Plus

The planned mobility project will further strengthen and institutionalize the already existing collaboration between Leiden University Medical Center (LUMC), Havana University and the Havana Medical Sciences University in Cuba. This mobility project with Cuba is in line with the general intention and strategy of Leiden University to create a more international student, to strengthen the international character of the University, to internationalize the learning experience for all students, and to extend our collaborative networks to other countries and regions. More specifically, the Leiden University Medical Center has chosen several countries to cooperate and Cuba is one of the designated countries. Cuba was selected due to its high level of preventive care and vaccine research (despite the impact of international sanctions on medicine and medical supplies, Cuban health outcomes are comparable to those of developed countries [2010, Science, 328, 572-573]).

The main reason for starting a mobility project in the framework of Erasmus+ KA1 is to make the mobility between the Netherlands and Cuba two-sided. The knowledge and skills available in both countries are of an equal level, but mobility is currently limited to staff and students going from Leiden to Havana, but not from Havana to Leiden. The project would greatly benefit from a more equal participation from both sides. Unfortunately, there are no funds available in Cuba for either the staff or student mobility to the Netherlands. Erasmus+ funding would enable such a mobility opportunity.

Within the project, the Cuban partners will design and develop new tools that are important for anti-cancer and vaccination strategies. These tools, developed by Cuban students, will be tested and optimized with in vitro/in vivo experiments at the Leiden University exploiting the state-of-the-art facilities, equipment and knowledge that is available at the LUMC. Therefore, the planned mobility project will be a unique experience for Cuban students. At the same time, the Cuban preventive health care system can also serve as an example for the Netherlands in its efforts to keep health care affordable.

Students from Havana have an excellent level in chemistry/biology and immunology. In Leiden they will be trained in immunology (LUMC) and in Nanotechnology and Molecular Imaging applied to immunology (Leiden Institute of Chemistry and Nanomedicine and Molecular Imaging at the Radiology Department from Leiden University Medical Center). Staff members from Havana will come to Leiden for training/teaching. Staff members from here will go to Havana only for teaching.

In Cuba they are developing new anti-bacterial vaccines based on polysaccharides. Here we will study a way to optimize the vaccine-efficacy. For this type of studies the facilities and expertise from LUMC are necessary, which include the immunology lab, cell culture and flow cytometry (expensive apparatus). In addition, Leiden will also develop a Nanotechnology approach based on the Cuban vaccines. To teach Cuban students all these new approaches and new areas of immunology and chemistry, staff from Leiden will go to Havana. In conclusion, we have a practical training based on new results (Cuban students here in Leiden), and a tutorial/teaching aim in Havana. The carbohydrate-vaccine field is new and the Cubans were pioneers in this field.

Head of TNI

Dr. Luis J. Cruz, head of TNI (Assistant Professor)

Researchers at TNI