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

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Scheid, Elizabeth, Major, Pierre, Bergeron, Alain, Finn, Olivera J., Salter, Russell D., Eady, Robin, Yassine-Diab, Bader, Favre, David, Peretz, Yoav, Landry, Claire, Hotte, Sebastien, Mukherjee, Som D., Dekaban, Gregory A., Fink, Corby, Foster, Paula J., Gaudet, Jeffery, Gariepy, Jean, Sekaly, Rafick-Pierre, Lacombe, Louis, Fradet, Yves, Foley, Ronan·2016·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-15-0189PMC PMC5331878

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Abstract

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 was mixed with an adjuvant or loaded on autologous dendritic cells (DC), and responses were compared. Unglycosylated rmMUC1 peptide induced negligible humoral or cellular responses compared with 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 nonmetastatic castrate-resistant prostate cancer (nmCRPC) were tested with a Tn-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. Cancer Immunol Res; 4(10); 881–92. ©2016 AACR.

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Metadata

Authors
Scheid, E., Major, P., Bergeron, A., Finn, O. J., Salter, R. D., Eady, R., Yassine-Diab, B., Favre, D., Peretz, Y., Landry, C., Hotte, S., Mukherjee, S. D., Dekaban, G. A., Fink, C., Foster, P. J., Gaudet, J., Gariepy, J., Sekaly, R.-P., Lacombe, L., Fradet, Y., & Foley, R.
Affiliations
  • McMaster University (CA)
  • Hamilton Health Sciences (CA)
  • Université Laval (CA)
  • University of Pittsburgh (US)
  • 6ImmuneCarta Inc., Montréal, Québec, Canada.
  • Québec-Océan (CA)
  • 2Hamilton Health Sciences, Hamilton, Ontario, Canada.
  • Robarts Research Institute (CA)
  • 7Robarts Research Institute, London, Ontario, Canada.
  • 8Sunnybrook Research Institute, Toronto, Ontario, Canada.
  • 9Université de Montréal, Montréal, Québec.
Corresponding author
Foley, Ronan
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2016-10-01
Volume
4
Issue
10
Pages
881-892
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-15-0189
PMC
PMC5331878
OpenAlex
W2510555501
Cited by
72
References
2
Citations by year
2026: 1 · 2025: 11 · 2024: 8 · 2023: 10 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 3
FWCI
2.75
Type
journal article
Language
en
Open access
Locations
  • Cancer Immunology Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA168392)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
Keywords
MUC1 glycopeptide, dendritic cell vaccination, castration-resistant prostate cancer, non-metastatic prostate cancer, tumor-associated antigens, rhesus macaque model, T cell response, PSA doubling time, vaccine safety, glycosylation
MeSH terms
Aged, Aged, 80 and over, Animals, Dendritic Cells, Feasibility Studies, Humans, Macaca mulatta, Male, Middle Aged, Vaccination, CD4-Positive T-Lymphocytes, Prostate-Specific Antigen, Mucin-1, CD8-Positive T-Lymphocytes, Cancer Vaccines, Prostatic Neoplasms, Castration-Resistant

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