A synthetic dendritic cell platform for immune activation

Contains fulltext : 194280.pdf (publisher's version ) (Open Access)Radboud University, 19 september 2018Promotor : Figdor, C.G. Co-promotores : Tel, J., Hammink, R.257 p

Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells

Contains fulltext : 137111.pdf (publisher's version ) (Open Access)Active anti-cancer immune responses depend on efficient presentation of tumor antigens and co-stimulatory signals by antigen-presenting cells (APCs). Therapy with autologous natural APCs is costly and time-consuming and results in variable outcomes in clinical trials. Therefore, development of artificial APCs (aAPCs) has attracted significant interest as an alternative. We discuss the characteristics of various types of acellular aAPCs, and their clinical potential in cancer immunotherapy. The size, shape, and ligand mobility of aAPCs and their presentation of different immunological signals can all have significant effects on cytotoxic T cell activation. Novel optimized aAPCs, combining carefully tuned properties, may lead to efficient immunomodulation and improved clinical responses in cancer immunotherapy

Dendritic cells in cancer immunotherapy

Item does not contain fulltex

Controlling T-Cell Activation with Synthetic Dendritic Cells Using the Multivalency Effect

Contains fulltext : 174408.pdf (publisher's version ) (Open Access)Artificial antigen-presenting cells (aAPCs) have recently gained a lot of attention. They efficiently activate T cells and serve as powerful replacements for dendritic cells in cancer immunotherapy. Focusing on a specific class of polymer-based aAPCs, so-called synthetic dendritic cells (sDCs), we have investigated the importance of multivalent binding on T-cell activation. Using antibody-functionalized sDCs, we have tested the influence of polymer length and antibody density. Increasing the multivalent character of the antibody-functionalized polymer lowered the effective concentration required for T-cell activation. This was evidenced for both early and late stages of activation. The most important effect observed was the significantly prolonged activation of the stimulated T cells, indicating that multivalent sDCs sustain T-cell signaling. Our results highlight the importance of multivalency for the design of aAPCs and will ultimately allow for better mimics of natural dendritic cells that can be used as vaccines in cancer treatment

Affinity-Based Purification of Polyisocyanopeptide Bioconjugates

Contains fulltext : 177944.pdf (publisher's version ) (Closed access)Water-soluble polyisocyanopeptides (PICs) are a new class of synthetic polymers that mimic natural protein-based filaments. Their unique semiflexible properties combined with a length of several hundred nanometers have recently enabled a number of biomedical applications ranging from tissue engineering to cancer immunotherapy. One crucial step toward the further development of PICs for these applications is the efficient and controlled synthesis and purification of PIC-biomolecule conjugates. Considering the large size of PICs and the biomolecules to be conjugated, conjugation reactions do usually not proceed to completion due to steric effects. As a consequence, purification of the reaction mixture is necessary to separate the obtained bioconjugates from unreacted biomolecules. As a direct result of the semiflexible nature of PICs, standard polymer and protein purification methods based on molecular weight have not been successful. Here, we introduce a new affinity-based purification method utilizing biotin as an affinity tag. PICs decorated with a controlled and tunable density of biotin molecules (biotinPICs) were efficiently bound to and eluted from a monoavidin resin in buffered aqueous solution. Using these biotinPICs, two different protein conjugates were synthesized, one carrying the enzyme alkaline phosphatase (PhoA) and the other T-cell activating anti-CD3 antibodies. The resulting biotinPIC-protein conjugates were successfully obtained in high purity (>90%) and without any loss of protein activity. The high purity greatly simplifies the analysis of biotinPIC bioconjugates, such as the determination of the average number of biomolecules conjugated per biotinPIC chain. Most importantly, it allows for the direct and straightforward application of the obtained bioconjugates in the desired applications. The new method developed may further be adapted for the purification of other advanced bioconjugates that are difficult to obtain in high purity with the available standard methods

Semiflexible Immunobrushes Induce Enhanced T Cell Activation and Expansion

Contains fulltext : 233607.pdf (Publisher’s version ) (Open Access

Injectable Biomimetic Hydrogels as Tools for Efficient T Cell Expansion and Delivery

Contains fulltext : 199026.pdf (publisher's version ) (Open Access)15 p

Dictating Phenotype, Function, and Fate of Human T Cells with Co-Stimulatory Antibodies Presented by Filamentous Immune Cell Mimics

T cells require a co-stimulatory signal in addition to T-cell receptor (TCR) stimulation to achieve full activation. While most studies focus on the co-stimulatory receptor CD28, little is known about the role of the other co-stimulatory receptors in T-cell signaling. A deeper understanding of how co-stimulatory receptor signaling cooperates with TCR signaling could improve the ability to control T-cell function and benefit the design of T-cell based immunotherapies. Artificial antigen presenting cells (aAPCs) enable tight control over the signals given to T cells. In this study, filamentous polyisocyanopeptide (PIC) polymers (immunofilaments) are used as nanosized aAPCs to study the role of the engagement of six distinct co-stimulatory molecules on human T-cell phenotype, function, and fate in the context of TCR signaling. The immunofilaments highlight important roles for CD28 and CD2 signaling in T-cell priming, proliferation, cytokine production, and multifunctionality. Taken together, this work provides insight into the role of combined TCR and co-stimulation on T-cell phenotype, function, and fate using immunofilaments. Notably, the findings on the roles of co-stimulatory molecule function can be used for the rational design of future cancer immunotherapies