Responsive hydrogels applied in the biomedical area show great potential as synthetic extracellular matrix mimics and as host medium for cell growth. The hydrogels often lack the characteristic mechanical properties that are typically seen for natural gels. Here, we demonstrate the unique responsive and mechanical properties of hydrogels based on oligo(ethylene glycol) functionalized polyisocyanopeptides. These stiff helical polymers form gels upon warming at concentrations as low as 0.006 %-wt polymer, with materials properties almost identical to those of their intermediate filaments, a class of cytoskeletal proteins. Using a combination of macroscopic rheology and molecular force microscopy the hierarchical relationship between the macroscopic behaviour of theses peptide mimics has been correlated with the molecular parameters.

A new class of antibody-functionalized, semi-flexible and filamentous polymers (diameter 5-10 nm, length $200 nm) with a controlled persistence length, a high degree of stereoregularity and the potential for multiple simultaneous receptor interactions has been developed. We have decorated these highly controlled, semi-stiff polymers with T cell activating anti-CD3 antibodies and analyzed their application potential as simple synthetic mimics of dendritic cells (sDCs). Our sDCs do not only activate T cells at significantly lower concentrations than free antibodies or rigid sphere-like counterparts (PLGA particles) but also induce a more robust T cell response. Our novel design further yields sDCs that are biocompatible and non-toxic. The observed increased efficacy highlights the importance of architectural flexibility and multivalency for modulating T cell response and cellular function in general.

Dendritic cells (DCs) are antigen-presenting cells that play an essential role in T cell activation. Recent efforts in cancer immunotherapy have been directed at the development of artificial antigen presenting cells (aAPCs) loaded with tumor antigens. These aAPCs are designed to mimic DCs with the goal of triggering an efficient and specific T cell response directed against the tumor. We have designed a novel synthetic dendritic cell (sDC) that possesses the essential features of natural DCs. Our sDC is based on a semiflexible poly(isocyano peptide) polymer and carries anti-CD3 antibodies (αCD3) for triggering the T cell receptor/CD3 complex as well as anti-CD28 antibodies (αCD28) as a co-stimulatory signal. Multiple copies of both antibodies facilitate multivalent binding similar to natural DCs. The high mobility of these polymer-bound antibodies, reminiscent of protein motility in a natural plasma membrane, enables receptor rearrangements to occur during T cell activation. We show that our bifunctional αCD3/αCD28-sDC triggers T cell activation at significantly lower antibody concentrations than freely soluble antibodies. This superior performance is further demonstrated in comparison to a mixture of monofunctional αCD3-sDC and αCD28-sDC. The presence of both antibodies on the same polymer not only reduces the threshold for T cell activation but, more importantly, critically shapes the specificity of the T cell response. αCD3/αCD28-sDC is a far more efficient activator of multifunctional killer cells. These findings demonstrate the potential of multifunctional polymers for mimicking natural DCs, paving the way for their exploitation in immunotherapeutic strategies.

Thermosensitive polymers show an entropy-driven transition from a well-solvated to a poorly solvated polymer chain, resulting in a more compact globular conformation. The transition at the lower critical solution temperature (LCST) is often sharp, which allows for a wide range of smart material applications. At the LCST, oligo(ethylene glycol)-substituted polyisocyanides (PICs) form soft hydrogels, composed of polymer bundles similar to biological gels, such as actin, fibrin and intermediate filaments. Here, we show that the LCST of PICs strongly depends linearly on the length of the ethylene glycol (EG) tails; every EG group increases the LCST and thus the gelation temperature by nearly 30 °C. Using a copolymerisation approach, we demonstrate that we can precisely tailor the gelation temperature between 10 °C and 60 °C and, consequently, tune the mechanical properties of the PIC gels.

Most cellular therapies targeting cancer require culture of autologous cells. The dedicated facilities and personnel needed, the variability in quality of the product depending on the condition of the patient and state of disease, hamper widespread use. In an attempt to generate an of the shelf product to target cancer we exploited the ever expanding possibilities to build supramolecular structures offered by chemistry to mimic nature including the construction of artificial immune cells or functions thereof. Effective immunotherapy critically depends on efficient production of antigen-specific cytotoxic T-cells. Herein lies an opportunity for both chemists and immunologists to design and synthesize so-called artificial antigen presenting cells (aAPCs) that can generate in vivo T-cell expansion. We have designed a novel synthetic dendritic cell (sDC) that possesses essential features of natural DCs. Our sDC is based on a semi-flexible poly(isocyano peptide) polymer and, as proof of principle, carries both anti-CD3 antibodies for triggering the T cell receptor/CD3 complex as well as anti-CD28 antibodies as a co-stimulatory signal. Multiple copies of both antibodies facilitate multivalent binding similar to natural DCs. The high mobility of these polymer-bound antibodies, reminiscent of protein motility in a natural plasma membrane, enables receptor rearrangements to occur during T cell activation. We observed effective T cell activation at significantly lower antibody concentrations than freely soluble antibodies. We also demonstrate antigen specific T cell activation when MHC/peptide complexes were bound. These findings demonstrate the potential of multifunctional polymers for mimicking functions of natural DCs or other immune cells, paving the way for their exploitation in immunotherapeutic strategies. Citation Format: Carl G. Figdor, Subhra Mandal, Roel Hammink, Loek Eggermont, Jorieke Weiden, Dion Voerman, Jurjen Tel, Zaskia H. Eksteen-Akeroyd, Kerstin Blank, Alan E. Rowan. Towards synthetic immune cells for cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA29.