Chapter 7 - TLR Ligand–Peptide Conjugate Vaccines: Toward Clinical Application
Introduction
Cancer is routinely treated by surgery, chemotherapy, and radiation. Although refinement of these therapies has resulted in considerably lower incidences of side effects with maintenance of efficacy, the call for better targeted therapies has become stronger. In recent years, considerable progress was achieved in the field of immunotherapy.
Several immunotherapeutic antibodies against cancer are on the market, while also tumor antigen-based specific vaccine formulations are currently being developed (Buonerba et al., 2011, Pedicord et al., 2011, Zarour and Ferrone, 2011).
Cancer patients often show detectable tumor-antigen specific T-cell immunity, but a process of tolerance seems to overpower the eradication of tumor cells. Several approaches to overcome or to modulate the tolerant or suppressed state of tumor-specific T-cells are in clinical studies now, like CTLA-4 and PD-1 blockade (Pedicord et al., 2011, Rosenblatt et al., 2011). Besides, there is much progress in optimizing vaccine formulations to more effectively prime or (re)activate tumor-specific T-cells. This review focuses on optimal vaccine formulations, in more detail on synthetically defined structures that harbor the right properties for specific T-cell activation.
To achieve a state of effective antitumor immunity, a triad of immune-related hallmarks can be defined. First, a therapy should be targeted against the central antigen-presenting cell (APC), the dendritic cell (DC). This goal can be met by making use of the broad array of receptors that DCs express. At the same time, a DC should be matured in such a way that a process is set into action that will ultimately lead to presentation of tumor antigens in their MHC class I or II molecules, combined with the upregulation of costimulatory molecules. Third, the antigen that is delivered to the DC should be highly tumor specific in order to achieve antitumor immunity and evade tolerance induction.
These three hallmarks can also potentially be combined in one molecule. Conjugating antigen to a targeting molecule, such as a Toll-like receptor ligand (TLR ligand), enables the efficient delivery of tumor-derived antigen to DCs while maturing these DCs to induce (cross-)presentation to tumor-specific T-helper cells (Th cells) and cytotoxic T-cells (CTLs) (Segura and Villadangos, 2009). It is well established that besides specific CTLs, also tumor-specific Th cells are essential for proper antitumor cellular immunity. This was already demonstrated in our group over a decade ago by immunizing mice with a peptide containing either a specific or an irrelevant Th epitope and subsequently inoculating these mice with a MHC class II negative tumor. Only mice that received the tumor-specific Th epitope-containing peptide were protected from tumor outgrowth. CD8+ T-cells were identified as the effector cells responsible for tumor eradication, while it was shown that CD4+ T-cells were not able to directly recognize the tumor cells but rather cross-presented tumor antigen by local MHC class II expressing APCs (Ossendorp et al., 1998). In the same period, it was firmly established in our and other groups that T help cells for CTL priming was mainly mediated by Th–DC cell–cell contact via the CD40–CD40L interaction (Bennett et al., 1998, Ridge et al., 1998, Schoenberger et al., 1998). Therefore, effective tumor-specific vaccines should include tumor antigen-specific Th and CTL epitope sequences.
Section snippets
Central role of DCs in vaccine development
DCs play a crucial role in the initiation and control of T-cell-mediated immune responses. In the peripheral tissues, DCs reside in an immature state where they sample antigens and pathogens from their surroundings. After antigen capture in the presence of a danger signal, such as bacterial unmethylated CpG DNA or LPS, DCs undergo a complex maturation process and in vivo the DCs home to the T-cell-rich areas of the lymphoid organs, where they present antigenic peptides to specific T-cells and
Synthetic Peptide Vaccination
From a historic vaccine development perspective, whole tumor cell lysates came to the attention of researchers as a putative novel treatment of cancer. Although enhanced T-cell responses and (temporary) remission of tumors were observed using tumor lysates or DCs pulsed with these lysates (Geiger et al., 2001, Ribas et al., 2010), the popularity of this technique has diminished as it lacks adequate specificity, and the obtained results have not led to a breakthrough. Also, vaccination with
Conjugation of Antigen to TLR Ligands
In a survey of the status of melanoma vaccines, the overall objective response rate in a series of 440 patients treated with various melanoma-specific vaccines was only 2.6% (Rosenberg et al., 2004). It was concluded that the immunotherapeutic approaches need drastic improvement. Since most peptide vaccination trials to date were carried out by injecting exact MHC class I binding peptides, often without TLR ligand, this evaluation is certainly justified. Measures for improved clinical results
Synergy between different PRR routes
A natural infection always brings forth a broad array of antigenic ligands, which can be recognized by divergent PRRs. For example, the bacterial cell wall harbors both TLR ligands, such as lipopeptides and lipoproteins, CLR ligands, such as (amino)sugars, as well as NLR ligands, such as muropeptides (MDP). Therefore, it seems plausible to combine multiple PRR ligands (PRR-Ls) in one molecule to even increase the potency of such conjugates.
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