Therapeutic cancer vaccines trigger CD4 + and CD8 + T cell responses capable of established tumor eradication. Current platforms include DNA, mRNA and synthetic long peptide (SLP) vaccines, all... Show moreTherapeutic cancer vaccines trigger CD4 + and CD8 + T cell responses capable of established tumor eradication. Current platforms include DNA, mRNA and synthetic long peptide (SLP) vaccines, all aiming at robust T cell responses. SLPs linked to the Amplivant (R) adjuvant (Amplivant-SLP) have shown effective delivery to dendritic cells, resulting in improved immunogenicity in mice. We have now tested virosomes as a delivery vehicle for SLPs. Virosomes are nanoparticles made from influenza virus membranes and have been used as vaccines for a variety of antigens. Amplivant-SLP virosomes induced the expansion of more antigen-specific CD8 + T memory cells in ex vivo experiments with human PBMCs than Amplivant-SLP conjugates alone. The immune response could be further improved by including the adjuvants QS-21 and 3D-PHAD in the virosomal membrane. In these experiments, the SLPs were anchored in the membrane through the hydrophobic Amplivant adjuvant. In a therapeutic mouse model of HPV16 E6/E7(+) cancer, mice were vaccinated with virosomes loaded with either Amplivant-conjugated SLPs or lipid-coupled SLPs. Vaccination with both types of virosomes significantly improved the control of tumor outgrowth, leading to elimination of the tumors in about half the animals for the best combinations of adjuvants and to their survival beyond 100 days. Show less
This thesis describes the development and immunological evaluation of two different cancer vaccination strategies for peptide-based personalized cancer vaccines. Both strategies, liposomal... Show moreThis thesis describes the development and immunological evaluation of two different cancer vaccination strategies for peptide-based personalized cancer vaccines. Both strategies, liposomal encapsulation and adjuvanting by direct conjugation to a TLR-ligand, are aimed to be readily combined with neoantigen-containing synthetic peptide sequences. In order to formulate such personalized cancer vaccines a flexible platform is required that can harbor a wide range of physiochemically different SPs, because multiple neoepitopes are uniquely expressed per patient. Upon formulation, the vaccination platform should be able to induce effective tumor-specific immune responses, which was evaluated in this thesis in in vitro and in vivo preclinical models. Show less
Cancer vaccines are aimed at raising an immune responses aganist defined tumor antigens. The formulation of a vaccine has a direct impact on the potency of the immune response generated. Cancer... Show moreCancer vaccines are aimed at raising an immune responses aganist defined tumor antigens. The formulation of a vaccine has a direct impact on the potency of the immune response generated. Cancer vaccines require particular effort in their formulation, as the immune system has to overcome immune suppression exerted by the tumor. In this thesis, different formulations to enhance cancer vaccine efficacy were explored. In the first part it is shown how chemical conjugation of antigen and adjuvant in form synthetic Toll-like receptor ligands represent a strategy to enahnce vaccine potency. Next, it is presented how the loading of peptide antigens onto dextran nanogel contributes to increase the breadth of the immune response induced. Lastly, a new DNA vaccine containing multiple tumor neoantigens was explored as a platform for personalized cancer vaccines. Together, these studies display how the formulation of cancer vaccines can be modified and optimized to achieve stronger therapeutic efficacy in the clinic. Show less
