Abstract
Immunotherapy has increased overall survival of metastatic cancer patients, and cancer antigens are promising vaccine targets. To fulfill the promise, appropriate tailoring of the vaccine formulations to mount in vivo cytotoxic T cell (CTL) responses toward co-delivered cancer antigens is essential. Previous development of therapeutic cancer vaccines has largely been based on studies in mice, and the majority of these candidate vaccines failed to induce therapeutic responses in the subsequent human clinical trials. Given that antigen dose and vaccine volume in pigs are translatable to humans and the porcine immunome is closer related to the human counterpart, we here introduce pigs as a supplementary large animal model for human cancer vaccine development. IDO and RhoC, both important in human cancer development and progression, were used as vaccine targets and 12 pigs were immunized with overlapping 20mer peptides spanning the entire porcine IDO and RhoC sequences formulated in CTL-inducing adjuvants: CAF09, CASAC, Montanide ISA 51 VG, or PBS. Taking advantage of recombinant swine MHC class I molecules (SLAs), the peptide-SLA complex stability was measured for 198 IDO- or RhoC-derived 9-11mer peptides predicted to bind to SLA-1*04:01, −1*07:02, −2*04:01, −2*05:02, and/or −3*04:01. This identified 89 stable (t½ ≥ 0.5 h) peptide-SLA complexes. By IFN-γ release in PBMC cultures we monitored the vaccine-induced peptide-specific CTL responses, and found responses to both IDO- and RhoC-derived peptides across all groups with no adjuvant being superior. These findings support the further use of pigs as a large animal model for vaccine development against human cancer.
Highlights
Therapeutic anti-cancer vaccines are expected to be important in the future immunotherapeutic treatment of cancer, either alone or in combination with, e.g., administration of drugs targeting the checkpoint inhibitors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) (Hodi et al, 2010; Brahmer et al, 2012; Topalian et al, 2012; Hamid et al, 2013; Wolchok et al, 2013)
The pigs were divided in four adjuvant groups receiving the 20mer peptide library formulated in either poly(I:C) decorated dimethyldioctadecylammonium (DDA)/monomycoloyl glycerol (MMG) cationic liposomes referred to as the cationic adjuvant formulation (CAF)09 (Korsholm et al, 2014), a porcine/human modification of the combined adjuvant for synergistic activation of cellular immunity (CASAC) containing CpG, monophosphoryl lipid A (MPL), IFNγ, CD40 ligand (CD40L), and CD40L enhancer in an oil/water formulation (Wells et al, 2008), Montanide ISA 51 Montanide ISA VG (VG) water/oil (Iversen et al, 2014) or phosphate buffered saline (PBS)
Previous studies have confirmed the involvement of CD8+ T cells in anti-cancer immune reactivity (Klebanoff et al, 2005; Sørensen et al, 2011b; Andersen, 2012; Joyce and Fearon, 2015; Rosenberg and Restifo, 2015) and anti-cancer vaccines are generally administered with the aim of enhancing this antigen- specific T-cell reactivity
Summary
Therapeutic anti-cancer vaccines are expected to be important in the future immunotherapeutic treatment of cancer, either alone or in combination with, e.g., administration of drugs targeting the checkpoint inhibitors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) (Hodi et al, 2010; Brahmer et al, 2012; Topalian et al, 2012; Hamid et al, 2013; Wolchok et al, 2013). The pigs were divided in four adjuvant groups receiving the 20mer peptide library formulated in either poly(I:C) decorated dimethyldioctadecylammonium (DDA)/monomycoloyl glycerol (MMG) cationic liposomes referred to as the cationic adjuvant formulation (CAF) (Korsholm et al, 2014), a porcine/human modification of the combined adjuvant for synergistic activation of cellular immunity (CASAC) containing CpG, monophosphoryl lipid A (MPL), IFNγ, CD40 ligand (CD40L), and CD40L enhancer in an oil/water formulation (Wells et al, 2008), Montanide ISA 51 VG water/oil (Iversen et al, 2014) (hereafter referred to as ISA 51 VG) or phosphate buffered saline (PBS) These adjuvants were chosen based on their previous ability to mount CTL responses in mouse and/or man. Stronger and more consistent responses are, warranted indicating the relevance of further studies on adjuvant and peptide dose, number of immunizations and more detailed characterization of the immunological response profile
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