Adjuvants for Enhancing the Immunogenicity of Whole Tumor Cell Vaccines

Abstract

Whole tumor cell lysates can serve as excellent multivalent vaccines for priming tumor-specific CD8(+) and CD4(+) T cells. Whole cell vaccines can be prepared with hypochlorous acid oxidation, UVB-irradiation and repeat cycles of freeze and thaw. One major obstacle to successful immunotherapy is breaking self-tolerance to tumor antigens. Clinically approved adjuvants, including Montanide™ ISA-51 and 720, and keyhole-limpet proteins can be used to enhance tumor cell immunogenicity by stimulating both humoral and cellular anti-tumor responses. Other potential adjuvants, such as Toll-like receptor agonists (e.g., CpG, MPLA and PolyI:C), and cytokines (e.g., granulocyte-macrophage colony stimulating factor), have also been investigated.

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…30 Second, after internalization by APCs, tumor cell debris facilitate cross-presentation of antigens to CD4C and CD8C T cells, thus generating long-term CD8C T cell memory with CD4C T cell help. 31 Antigenic peptides expressed inside cells and/or on the cell surface are generally more immunogenic than the same peptides in a soluble unbound form. In fact, the immune system is better adapted to combat cells bearing an infectious or cancerous danger signals, compared with the relatively safe soluble products.…”

“…Therefore, to enhance vaccine immunogenicity, tumor cell-based vaccines can be modified to secrete pro-inflammatory cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF), which could facilitate recruitment of DCs at the site of vaccine administration. 31 Vaccination with tumor cells genetically modified for IL-12 production (a key cytokine boosting Th1 immunity) has been shown to cause a significant tumor suppression in mice paralleled with high IFN-g production and activation of CTL and NK cells. 12,39 Normally, tumor cells are devoid of molecules that could co-stimulate TAA-specific T cells.…”

“…Published data indicate that necrotic tumor cells can promote DC maturation, 32 possibly because dead cells release heat shock proteins (HSP), such as HSP 70 and 90, the pro-inflammatory factor high mobility group box 1 (HMGB1), and pro-inflammatory cytokines. 31 Furthermore, RNA and DNA of injured cells are rapidly degraded to purine bases, with subsequent convertion into uric acid (an end product of the purine metabolic pathway), which can serve as a critical endogenous danger signal driving DC maturation. 31,33 Table 3 presents the characteristics of various types of cell-based vaccines.…”

“…31 Furthermore, RNA and DNA of injured cells are rapidly degraded to purine bases, with subsequent convertion into uric acid (an end product of the purine metabolic pathway), which can serve as a critical endogenous danger signal driving DC maturation. 31,33 Table 3 presents the characteristics of various types of cell-based vaccines.…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…A large majority of these studies involve either short TAA-derived peptides that can directly bind to MHC Class I or II molecules expressed by antigen-presenting cells 176 (42 studies), or SLPs that are processed intracellularly and then loaded on MHC Class I or II molecules 172,177,178 (22 studies), most often in combination with immunological adjuvants 179-182 like montanide ISA-51 (water-in-oil emulsion) 181,183 Hiltonol® (poly- L -lysine in carboxymethylcellulose, a TLR3 ligand) 184 and GM-CSF. 183,185-187 In several instances, vaccination is further combined with standard treatment regimens including conventional chemotherapy, 117,188-191 radiation therapy, 52,192-195 and targeted anticancer agents, 196-199 or with various immunotherapeutic interventions.…”