Synthetic Cancer Vaccines Research Articles

Robust Antigen-Specific T Cell Activation within Injectable 3D Synthetic Nanovaccine Depots.

Synthetic cancer vaccines may boost anticancer immune responses by co-delivering tumor antigens and adjuvants to dendritic cells (DCs). The accessibility of cancer vaccines to DCs and thereby the delivery efficiency of antigenic material greatly depends on the vaccine platform that is used. Three-dimensional scaffolds have been developed to deliver antigens and adjuvants locally in an immunostimulatory environment to DCs to enable sustained availability. However, current systems have little control over the release profiles of the cargo that is incorporated and are often characterized by an initial high-burst release. Here, an alternative system is designed that co-delivers antigens and adjuvants to DCs through cargo-loaded nanoparticles (NPs) incorporated within biomaterial-based scaffolds. This creates a programmable system with the potential for controlled delivery of their cargo to DCs. Cargo-loaded poly(d,l-lactic-co-glycolic acid) NPs are entrapped within the polymer walls of alginate cryogels with high efficiency while retaining the favorable physical properties of cryogels, including syringe injection. DCs cultured within these NP-loaded scaffolds acquire strong antigen-specific T cell-activating capabilities. These findings demonstrate that introduction of NPs into the walls of macroporous alginate cryogels creates a fully synthetic immunostimulatory niche that stimulates DCs and evokes strong antigen-specific T cell responses.

Fully synthetic Mincle-dependent self-adjuvanting cancer vaccines elicit robust humoral and T cell-dependent immune responses and protect mice from tumor development.

A new strategy based on a macrophage-inducible C-type lectin (Mincle) agonist was established to construct synthetic cancer vaccines. Using sialyl-Tn (STn) as a model antigen, four conjugates with the Mincle agonist as a built-in adjuvant were designed and synthesized through a facile and efficient method. All conjugates could induce BMDMs to produce inflammatory cytokines in a Mincle-dependent manner and were found to elicit robust humoral and T cell-dependent immune responses alone in mice. The corresponding antibodies could recognize, bind and exhibit complement-dependent cytotoxicity to STn-positive cancer cells, leading to tumor cell lysis. Moreover, all conjugates could effectively inhibit tumor growth and prolong the mice survival time in vivo, with therapeutic effects better than STn-CRM197/Al. Notably, compared to conventional glycoprotein conjugate vaccines, these fully synthetic conjugate vaccines do not cause “epitope suppression.” Mincle ligands thus hold great potential as a platform for the development of new vaccine carriers with self-adjuvanting properties for cancer treatment. Preliminary structure–activity relationship analysis shows that a vaccine containing one STn antigen carried by vizantin exhibits the best efficacy, providing support for further optimization and additional investigation into Mincle agonists as the carrier of self-adjuvanting cancer vaccines.

Recent advances in carbohydrate-based cancer vaccines.

Cancer is a complex multifactorial disease for which many promising therapeutic strategies such as immunotherapy are emerging. Malignant cells frequently express aberrant cell surface carbohydrates, which differentiate them from normal "healthy" cells. This characteristic presents a window for the development of synthetic carbohydrate antigen-based cancer vaccines which can be recognized by the immune system and can bring about T cell-dependent immune responses. Antibodies generated against the carbohydrate antigens partake in the inactivation of carbohydrate-decorated cancer cells, by slowing down tumor cell growth and inducing cancer cell apoptosis. Novel synthetic strategies for carbohydrate antigens have led to several synthetic cancer vaccine candidates. In the present review, we describe the latest progress in carbohydrate-based cancer vaccines and their clinical evaluation in various cancers.

Synthesis of a conjugate of 3´-sialyllactoside with recombinant flagellin as a carrier protein and assessment of its immunological activity in comparison with that of a similar hemocyanin-based conjugate

In the framework of a project directed to the design of synthetic cancer vaccines based on carbohydrate chains of tumor-associated gangliosides, a new prototype cancer vaccine, a polyvalent carbohydrate-protein conjugate 1 with ∼11 3´-sialyllactoside ligands conjugated to one molecule of recombinant flagellin was synthesized. Dendritic cell vaccines were designed using the conjugate 1 and a neoglycoconjugate 2 consisting of ∼400 3´-sialyllactose residues linked to hemocyanin from a snail Megathura crenulata (KLH). Comparative ELISA study was conducted to assess the induction of carbohydrate-specific immunoglobulins IgM and IgG after immunization of mice with conjugates 1 and 2 and dendritic cells loaded with 1 and 2. Synthetic polyacrylamide carrier conjugated to 3´-sialyllactose ligands and B16F0 melanoma cells were used as coating antigens.

'Multicopy multivalent' glycopolymer-stabilized gold nanoparticles as potential synthetic cancer vaccines.

Mucin-related carbohydrates are overexpressed on the surface of cancer cells, providing a disease-specific target for cancer immunotherapy. Here, we describe the design and construction of peptide-free multivalent glycosylated nanoscale constructs as potential synthetic cancer vaccines that generate significant titers of antibodies selective for aberrant mucin glycans. A polymerizable version of the Tn-antigen glycan was prepared and converted into well-defined glycopolymers by Reversible Addition–Fragmentation chain Transfer (RAFT) polymerization. The polymers were then conjugated to gold nanoparticles, yielding ‘multicopy-multivalent’ nanoscale glycoconjugates. Immunological studies indicated that these nanomaterials generated strong and long-lasting production of antibodies that are selective to the Tn-antigen glycan and cross-reactive toward mucin proteins displaying Tn. The results demonstrate proof-of-concept of a simple and modular approach toward synthetic anticancer vaccines based on multivalent glycosylated nanomaterials without the need for a typical vaccine protein component.

Increasing the Antigenicity of Synthetic Tumor‐Associated Carbohydrate Antigens by Targeting Toll‐Like Receptors

SYNTHETIC CANCER VACCINES: A number of fully synthetic vaccine candidates have been designed, chemically synthesized, and immunologically evaluated to establish a strategy to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides and to determine the importance of Toll-like receptor (TLR) engagement for antigenic responses against these compounds.Epithelial cancer cells often overexpress mucins that are aberrantly glycosylated. Although it has been realized that these compounds offer exciting opportunities for the development of immunotherapy for cancer, their use is hampered by the low antigenicity of classical immunogens composed of a glycopeptide derived from a mucin conjugated to a foreign carrier protein. We have designed, chemically synthesized, and immunologically evaluated a number of fully synthetic vaccine candidates to establish a strategy to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides. The compounds were also designed to allow study of the importance of Toll-like receptor (TLR) engagement for these antigenic responses in detail. We have found that covalent attachment of a TLR2 agonist, a promiscuous peptide T-helper epitope, and a tumor-associated glycopeptide gives a compound (1) that elicits in mice exceptionally high titers of IgG antibodies that recognize MCF7 cancer cells expressing the tumor-associated carbohydrate. Immunizations with glycolipopeptide 2, which contains lipidated amino acids instead of a TLR2 ligand, gave significantly lower titers of IgG antibodies; this demonstrates that TLR engagement is critical for optimum antigenic responses. Although mixtures of compound 2 with Pam(3)CysSK(4) (3) or monophosphoryl lipid A (4) elicited titers of IgG antibodies similar to those seen with 1, the resulting antisera had impaired ability to recognize cancer cells. It was also found that covalent linkage of the helper T-epitope to the B-epitope is essential, probably because internalization of the helper T-epitope by B-cells requires assistance of the B-epitope. The results presented here show that synthetic vaccine development is amenable to structure-activity relationship studies for successful optimization of carbohydrate-based cancer vaccines.

Fully synthetic cancer vaccine shows promising results in mice

Fully synthetic cancer vaccine shows promising results in mice

Efficient metabolic engineering of GM3 on tumor cells by N-phenylacetyl-D-mannosamine.

Abnormal carbohydrates expressed on tumor cells, which are termed tumor-associated carbohydrate antigens (TACAs), are potential targets for the development of cancer vaccines. However, immune tolerance to TACAs has severely hindered progress in this area. To overcome this problem, we have developed a novel immunotherapeutic strategy based on synthetic cancer vaccines and metabolic engineering of TACAs on tumor cells. One critical step of this new strategy is metabolic engineering of cancer, namely, to induce expression of an artificial form of a TACA by supplying tumors with an artificial monosaccharide precursor. To identify the proper precursor for this application, N-propionyl, N-butanoyl, N-isobutanoyl, and N-phenylacetyl derivatives of d-mannosamine were synthesized, and their efficiency as biosynthetic precursors in modifying sialic acid and inducing expression of modified forms of GM3 antigen on tumor cells was investigated. For this purpose, tumor cells were incubated with different N-acyl-d-mannosamines, and modified forms of GM3 expressed on tumor cells were analyzed by flow cytometry using antigen-specific antisera. N-Phenylacetyl-d-mannosamine was efficiently incorporated in a time- and dose-dependent manner to bioengineer GM3 expression by several tumor cell lines, including K562, SKMEL-28, and B16-F0. Moreover, these tumor cell lines also exhibited ManPAc-dependent sensitivity to cytotoxicity mediated by anti-PAcGM3 immune serum and complement. These results provide an important validation for this novel therapeutic strategy. Because N-phenylacetyl GM3-protein conjugates are particularly immunogenic, the combination of an N-phenylacetyl GM3 conjugate vaccine with systemic N-phenylacetyl-d-mannosamine treatment is a promising immunotherapy for future development and application to melanoma and other GM3-bearing tumors.

Synthetic Cancer vaccine in prospect

Synthetic Cancer vaccine in prospect