Recent Advance in Tumor-associated Carbohydrate Antigens (TACAs)-based Antitumor Vaccines

Abstract

Cancer cells can be distinguished from normal cells by displaying aberrant levels and types of carbohydrate structures on their surfaces. These carbohydrate structures are known as tumor-associated carbohydrate antigens (TACAs). TACAs were considered as promising targets for the design of anticancer vaccines. Unfortunately, carbohydrates alone can only evoke poor immunogenicity because they are unable to induce T-cell-dependent immune responses, which is critical for cancer therapy. Moreover, immunotolerance and immunosuppression are easily induced by using natural occurring TACAs as antigens due to their endogenous property. This review summarizes the recent strategies to overcome these obstacles: (1) covalently coupling TACAs to proper carriers to improve immunogenicity, including clustered or multivalent conjugate vaccines, (2) coupling TACAs to T-cell peptide epitopes or the built-in adjuvant to form multicomponent glycoconjugate vaccines, and (3) developing vaccines based on chemically modified TACAs, which is combined with metabolic engineering of cancer cells.

Targeting cancer-specific glycans by cyclic peptide lectinomimics

“…Significant efforts have been undertaken to produce glycan-specific antibodies (Dalziel et al 2014; Fuster and Esko 2005) However, these have been difficult, as glycans are poor immunogens often resulting in weak affinity IgM antibodies with limited clinical value and low specificity of existing antibodies (Pinho and Reis 2015; Sterner et al 2016) One of the most promising and the most widely explored tumor-associated glycan structures in many diagnostic and (immuno)therapeutic approaches are truncated mucin-type O -glycans such as Tn (αGalNAc-Thr/Ser), sTn (αNeu5Ac-(2,6)-αGalNAc-Thr/Ser), and T (Galβ1-3GalNAcα1- O -Ser/Thr) (Cazet et al 2010) The major protein carrier of these tumor-associated glycans is the MUC1 glycoprotein, highly expressed in a variety of epithelial cancers, but absent from normal tissues (Nath and Mukherjee 2014) Despite the great potential, the generation of clinically relevant human antibodies with good affinity and specificity for tumor-associated glycans of MUC1 proves to be a challenging task (Loureiro et al 2015; Feng et al 2016) Identification of MUC1 glycan/peptide epitopes within a MUC1 tandem repeat, which are able to overcome immunological self-tolerance and yet induce stronger and long-lasting immune response is the current focus of immunotherapy approaches (McDonald et al 2015; Hossain and Wall 2016) An excellent example of such approaches is the PankoMab-GEX, a humanized monoclonal antibody that binds to a novel carbohydrate-induced conformational epitope on MUC1 (glycopeptide epitope) with a high affinity, which is currently undergoing clinical trials for ovarian cancer (Fiedler et al 2016)…”

Historical and Clinical Experiences of Gene Therapy for Solid Cancers in China

“…Furthermore, we could customize a more precise reagent of gene therapy for a single patient, based on the results of microarrays, to increase the therapeutic effect. Thirdly, by using vaccines which target tumor-associated antigens (TAA), immunotherapy may be a novel treatment strategy for cancer patients [73], which could be combined with gene therapy, such as p53 mutation in cancer cells. Although p53 mutations may represent the characteristics of TAA, most of the mutations do not occur at sites that correspond to immunological epitopes [74].…”

A unique mid-sequence linker used to multimerize the lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1

“…Natural (e.g., antibodies) and synthetic multivalent molecular peptides[1-3], peptidomimetics (such as peptoids[4-6]), carbohydrates[7-9], and small molecules[10, 11], present multiple copies of a receptor-binding element, which can therefore bind with high avidity and specificity. [9, 12-17] These can interact with receptors via chelating effects, receptor clustering, subsite binding, and statistical rebinding, all of which can lead to an improved affinity.…”

“…For almost all of the cases, the homo- or hetero-multimer linkers was either on the C- or N-terminus of the individual monomeric peptide or peptidomimetic units. [1, 3-6, 12, 20, 21]. In this study, we report a unique multimerization procedure using a lipid-phosphatidylserine (PS)-targeted peptide-peptoid hybrid (PPS1)[4, 22] containing linkers built into the internal region of the monomeric sequence.…”