Final Report Summary - GLYCOTREAT (Novel vaccine generation for the treatment of cancer. A glyco-nanomedial approach instructing T cells) The Glycotreat project aims to develop new glycan based nanomedicines to target to DC (DC-SIGN) and LC (Langerin) for theinduction of powerful T-cell responses to treat cancer. In this project we focus on various tumor types; melanoma, colon, gioblastoma and pancreatic cancer, that show differential sensisitvity to immune surveillanceThe project is divided into 3 work packages:1. Glyco-chemical design and generation of nanomedicine.2. The effective in situ activity of the vaccines in a human skin model.3. The in-vivo activation of the nanomedicines to activate tumor specific CD4 and CD8 T-cellresponses.The main question addressed in the Glycotreat project was can we design a glycan based nanomedicine that targets multiple skin resident DC/LC for the enhanced induction of anti-tumor T cells that eradicate tumors. The task of the members was to design various synthetic long peptides (SLP) that contained tumor epitopes to be presented in MHC class I and II for presentation to CD8 and CD4 T cells. Formulations altered in type of glycan, multivalency, lipidation, or inclusion in liposomes. Specificity for receptor (DC-SIGN/Langrin) was tested, uptake by human skin DC/LC, intracellular routing and induction of T cell responses in-vitro and in-vivo.Via this selection procedure we started with testing multiple glycan modified nanomedices and came to two products that were very effective in both DC-SIGN/Langerin targeting and induction of broad APC induction for T cell induction, which are G3-LewisY-MAPS, which has a multimerizing glycans for targeting, inclusion of multiple SLPs which can be used for effective melanoma induced CD4 and CD8 T cell responses, both in human skin, and in-vivo mouse models.The other formulation is lipidation of SLP (without a glycan) that targets any APC of choice, and also very effectively stimulated both CD4 and CD8 T cell responses, as well as its duration and quality. In the melanoma B16 model we have shown that therapeutic vaccination with Lewis-modified antigens eradicate tumors when combined with Treg removal, indicating that tumor induced suppression is hampering the effectiveness of vaccination. This illustrates that DC targeted vaccination needs to be tested in combination therapy. We started to do this in both the B16 and MC38 tumor model in mice, with anti-PD1 treatments. Moreover we analysed further which adjuvant would work synergistically with the glycan modified nanomedicines, showing Addavax and DC stimulation with anti-CD40 as the most optimal setting for DC targeted vaccines. We also have set up two orthotopic tumor models for PDAC and GBM for exploration of new immune suppressive leads in the tumor microenvironment, carbohydrate based, and to combine this with the glycan modified nanomedicines.
