One of the main challenges in the development of an effective anti-cancer vaccine is the generation of an adequate and directed cellular immune response. Antigen presenting cells play an important... Show moreOne of the main challenges in the development of an effective anti-cancer vaccine is the generation of an adequate and directed cellular immune response. Antigen presenting cells play an important role in obtaining such immune responses as they express pathogen recognition receptors (PRRs), for example Toll-like receptors (TLRs) and Nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), and Fc receptors. This enables them to recognize pathogen associated molecular patterns (PAMPs). A promising strategy in immunotherapy is the use of PRR ligands or antibody-recruiting molecules (ARMs) that are covalently bound to an antigenic peptide. The research in this Thesis describes the design and synthesis of new carbohydrate ligands and conjugates for TLR4, NOD2 and mannose-6-phosphate receptor (MPR) in which these ligands are covalently bound to antigenic peptides. In the second part of this Thesis, Fc receptors are exploited as they bind to an immune complex, which is formed by binding of an antibody to an ARM. Therefore several C-glycosyl lysine building blocks are designed and synthesized of which C-rhamnose was conjugated several times to an antigenic peptide. Show less
Immunotherapy of cancer has established itself in recent years as a promising novel approach to treat cancer patients. One of the experimental approaches is based on therapeutic vaccination. We... Show moreImmunotherapy of cancer has established itself in recent years as a promising novel approach to treat cancer patients. One of the experimental approaches is based on therapeutic vaccination. We have previously developed vaccines consisting of synthetic long peptides (SLP) which successfully eradicated premalignant lesions in 50% of patients. To further improve these vaccines, a Toll-like receptor ligand (TLR-L) was conjugated to SLP which enables targeting of the SLP to relevant antigen-presenting cells while concomitantly activating these cells. In fact, the research described in this thesis shows that TLR-L SLP conjugates induce enhanced antitumor immunity. Furthermore, optimization of the TLR-L led to even furher improved antitumor responses in mice. Using human cancer patient-derived lymph node cells, we show that lymph node-derived T cells are favorably activated by the TLR-L SLP conjugates. Finally, we combine multiple innate immune stimulatory agonists (TLR2-L and NOD2-L) in one molecule to establish synergistic immune activation. Overall, the research described in this thesis demonstrates the potency of TLR-L SLP conjugates as cancer vaccines, which could strongly contribute to the treatment of cancer patients. Show less