Tumor-Associated Glycans and Immune Surveillance

Monzavi‐Karbassi, Behjatolah; Pashov, Anastas; Kieber‐Emmons, Thomas

doi:10.3390/vaccines1020174

Cited by 48 publications

(40 citation statements)

References 186 publications

(224 reference statements)

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“…Cell transformation leads to MUC1 becoming hypersialylated and hypoglycosylated with truncated oligosaccharide chains such as GalNAc-Gal-α-O-Ser/Thr, (T antigen) or GalNAc-α-O-Ser/Thr (Tn antigen) (18). These carbohydrates along with T and Tn glycopeptides trigger immune recognition of the unglycosylated peptide backbone and the spontaneous development of low titer antibodies to MUC1 and low frequency MUC1-specific cytotoxic T lymphocytes (CTLs) (19–21). Active immunotherapy has the potential to enhance these immune responses or elicit de novo responses in patients with adenocarcinoma (20, 21).…”

Section: Introductionmentioning

confidence: 99%

Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate-Resistant Prostate Cancer

Scheid

Major

Bergeron

et al. 2016

Cancer Immunology Research

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MUC1 is a glycoprotein expressed on the apical surface of ductal epithelial cells. Malignant transformation results in loss of polarization and overexpression of hypoglycosylated MUC1 carrying truncated carbohydrates known as T or Tn tumor antigens. Tumor MUC1 bearing Tn carbohydrates (Tn-MUC1) represent a potential target for immunotherapy. We evaluated the Tn-MUC1 glycopeptide in a human phase I/II clinical trial for safety that followed a preclinical study of different glycosylation forms of MUC1 in rhesus macaques, whose MUC1 is highly homologous to human MUC1. Either unglycosylated rhesus macaque MUC1 peptide (rmMUC1) or Tn-rmMUC1 glycopeptide were mixed with an adjuvant, or loaded on autologous dendritic cells (DCs), and responses compared. Unglycosylated rmMUC1 peptide induced negligible humoral or cellular responses compared to the Tn-rmMUC1 glycopeptide. Tn-rmMUC1 loaded on DCs induced the highest anti-rmMUC1 T-cell responses and no clinical toxicity. In the phase I/II clinical study, 17 patients with non-metastatic castrate-resistant prostate cancer (nmCRPC) were tested with aTn-MUC1 glycopeptide-DC vaccine. Patients were treated with multiple intradermal and intranodal doses of autologous DCs, which were loaded with the Tn-MUC1 glycopeptide (and KLH as a positive control for immune reactivity). PSA doubling time (PSADT) improved significantly in 11 of 16 evaluable patients (P = 0.037). Immune response analyses detected significant Tn-MUC1-specific CD4+ and/or CD8+ T-cell intracellular cytokine responses in 5 out of 7 patients evaluated. In conclusion, vaccination with Tn-MUC1-loaded DCs in nmCRPC patients appears to be safe, able to induce significant T-cell responses, and have biological activity as measured by the increase in PSADT following vaccination.

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Section: Introductionmentioning

confidence: 99%

Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate-Resistant Prostate Cancer

Scheid

Major

Bergeron

et al. 2016

Cancer Immunology Research

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“…Despite much effort dedicated to improve anti-TACA antibody responses, 11–14 no TACA-based vaccines have been approved by FDA yet. Phase III studies of GM2–KLH and STn–KLH have failed to show therapeutic benefits even though significant antibody titers were stimulated in cancer patients.…”

mentioning

confidence: 99%

“…11–14 One potential complexity in TACAbased vaccine design is the heterogeneities of local environments of TACAs on tumor cell surfaces. Antibody recognition of the TACA epitope can be influenced by the glycoprotein sequence, 17,18 lipid structures of glycolipids, 19–21 or neighboring carbohydrates of the TACAs.…”

mentioning

confidence: 99%

Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine

et al. 2015

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Development of an effective vaccine targeting tumor associated carbohydrate antigens (TACAs) is an appealing approach toward tumor immunotherapy. While much emphasis has been typically placed on generating high antibody titers against the immunizing antigen, the impact of immunogen design on the diversity of TACA-specific antibodies elicited has been overlooked. Herein, we report that the immunogen structure can significantly impact the breadth and the magnitude of humoral responses. Vaccine constructs that induced diverse TACA-binding antibodies provided much stronger recognition of a variety of Tn positive tumor cells. Optimization of the breadth of the antibody response led to a vaccine construct that demonstrated long lasting effcacy in a mouse tumor model. After challenged with the highly aggressive TA3Ha cells, mice immunized with the new construct exhibited a statistically significant improvement in survival relative to controls (0% vs 50% survival; p < 0.0001). Furthermore, the surviving mice developed long-term immunity against TA3Ha. Thus, both the magnitude and the breadth of antibody reactivity should be considered when designing TACA-based antitumor vaccines.

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“…Cancer cells can be distinguished from normal cells through aberrant types and numbers of glycans on cells surface, which may result from glycosyltransferases and glycosidases abnormally expressed in tumor cells …”

Section: Tumor‐associated Carbohydrate Antigensmentioning

confidence: 99%

Carbohydrate‐based vaccines for oncotherapy

Wei

Wang

2018

Medicinal Research Reviews

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Cancer is still one of the most serious threats to human worldwide. Aberrant patterns of glycosylation on the surface of cancer cells, which are correlated with various cancer development stages, can differentiate the abnormal tissues from the healthy ones. Therefore, tumor-associated carbohydrate antigens (TACAs) represent the desired targets for cancer immunotherapy. However, these carbohydrate antigens may not able to evoke powerful immune response to combat with cancer for their poor immunogenicity and immunotolerance. Different approaches have been developed to address these problems. In this review, we want to summarize the latest advances in TACAs based anticancer vaccines.

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Tumor-Associated Glycans and Immune Surveillance

Cited by 48 publications

References 186 publications

Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate-Resistant Prostate Cancer

Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate-Resistant Prostate Cancer

Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine

Carbohydrate‐based vaccines for oncotherapy

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