Poly(I:C) as cancer vaccine adjuvant: Knocking on the door of medical breakthroughs
Introduction
To this date, an effective cure remains an elusive goal in many cancers, due to the complexity of tumor cells and their microenvironment. One of the recently acknowledged hallmarks of cancer is its evasion of immune-mediated destruction (Hanahan & Weinberg, 2011). In active cancer immunotherapy, including cancer vaccination, reversing this evasion is endeavored by modulating the host immune system in vivo to provoke an effective anti-tumor response.
Standard components of cancer vaccines are tumor-associated antigens (TAA) and immunostimulatory adjuvants (Coffman et al., 2010). Unfortunately, aluminum compounds as the most widely used vaccine adjuvants are very effective at promoting humoral immune responses, but fail to induce cell-mediated immunity, which is crucial for tumor elimination (Brewer, 2006). In contrast, pathogen-associated molecular patterns have a high capacity to stimulate cell-mediated immunity and are therefore thoroughly investigated as adjuvants in cancer vaccines. For example, the first FDA licensed adjuvant molecule monophosphoryl lipid A – a modified derivative of lipopolysaccharide – was shown to promote immune response broadening (Dubensky & Reed, 2010) and is now a component of an approved cervical cancer vaccine (Schwarz, 2009). This encourages the investigation of the adjuvant effects of other pathogen-associated molecular patterns, including double stranded RNA (dsRNA).
Polyriboinosinic–polyribocytidylic acid (poly(I:C)) and its derivative poly-ICLC (Hiltonol™, i.e. poly(I:C) stabilized with poly-l-lysine and carboxymethylcellulose) are synthetic mimics of viral dsRNA polymers with similar mechanism of action and are included in the National Cancer Institute's ranking of immunotherapeutic agents with the highest potential to boost cancer immunotherapy outcome (Cheever, 2008). Various strategies to include poly(I:C)/poly-ICLC in cancer vaccination are currently being investigated aiming to maximize the stimulation of anti-tumor immunity. In this review, we discuss the biological rationale, as well as the preclinical and clinical experience with poly(I:C) and poly-ICLC as cancer vaccine adjuvants.
Section snippets
Rationale for the use of poly(I:C) and poly-ICLC as cancer vaccine adjuvant
As a dsRNA analog, poly(I:C) is a ligand of the endosomal Toll-like receptor (TLR)3 (Cheever, 2008). This receptor is widely expressed in hematopoietic and non-hematopoietic cells, however reports are conflicting. In human immune cells, TLR3 was reported to be exclusively expressed by immature myeloid dendritic cells (DC), i.e. induced by differentiation from monocytes and decreased during maturation (Muzio et al., 2000). However, others have shown expression of TLR3 in additional immune cell
Preclinical results of poly(I:C)/poly-ICLC as cancer vaccine adjuvant
Several preclinical and clinical studies have been conducted to determine the safety and efficacy of poly(I:C)/poly-ICLC administration as cancer vaccine adjuvant (Table 1, Table 2, Table 3).
As shown in Table 1, the addition of poly(I:C)/poly-ICLC as single adjuvant to the different antigen formulations, i.e. cell-based, peptide or protein, exosome, or viral vaccines, resulted in enhanced induction of TAA-specific and functional T cells (in terms of IFN-γ production and/or tumor cell lysis).
Clinical experience with poly-ICLC
Early clinical studies using poly(I:C) as stand-alone agent to treat cancer date back to the seventies, but failed to present a beneficial effect of poly(I:C) on clinical outcome (Feldman et al., 1975, Robinson et al., 1976, Herr et al., 1978), probably due to its short half-life (<30 min) (Levy et al., 1975). Its stabilized form poly-ICLC proved to be 5- to 10-fold more resistant to hydrolysis in primate serum and induced significant serum levels of IFN (Levy et al., 1975, Levine et al., 1979).
Discussion
As an adjuvant, poly(I:C) is able to target tumor cells and immune cells directly and to activate immune cells and processes indirectly. Preclinical studies using poly(I:C)/poly-ICLC as cancer vaccine adjuvant showed promising results, both alone or when combined with other adjuvants (Table 1, Table 2). Compared to the vaccine counterparts without poly(I:C)/poly-ICLC, addition of the dsRNA molecule resulted in the improvement of tumor-specific immune responses as well as in better tumor
Conflict of interest statement
The authors declare that there are no conflicts of interest.
The following are the supplementary data related to this article.
Acknowledgments
This work was supported by research grants of the Research Foundation Flanders (FWO) and the University of Antwerp (BOF). YW was supported by a fellowship of the Agency for Innovation by Science and Technology (IWT).
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