Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate-Resistant Prostate Cancer.
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.
McMaster University, Hamilton, Ontario, Canada.
Elizabeth
E
Scheid
McMaster University, Hamilton, Ontario, Canada. Hamilton Health Sciences, Hamilton, Ontario, Canada.
Pierre
P
Major
Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada. Centre de Recherche sur le Cancer de l'Université Laval, Québec, Canada.
Alain
A
Bergeron
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Olivera J
OJ
Finn
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Russell D
RD
Salter
Hamilton Health Sciences, Hamilton, Ontario, Canada.
Robin
R
Eady
ImmuneCarta Inc., Montréal, Québec, Canada.
Bader
B
Yassine-Diab
ImmuneCarta Inc., Montréal, Québec, Canada.
David
D
Favre
ImmuneCarta Inc., Montréal, Québec, Canada.
Yoav
Y
Peretz
ImmuneCarta Inc., Montréal, Québec, Canada.
Claire
C
Landry
Hamilton Health Sciences, Hamilton, Ontario, Canada.
Sebastien
S
Hotte
Hamilton Health Sciences, Hamilton, Ontario, Canada.
Som D
SD
Mukherjee
Robarts Research Institute, London, Ontario, Canada.
Gregory A
GA
Dekaban
Robarts Research Institute, London, Ontario, Canada.
Corby
C
Fink
Robarts Research Institute, London, Ontario, Canada.
Paula J
PJ
Foster
Robarts Research Institute, London, Ontario, Canada.
Jeffery
J
Gaudet
Sunnybrook Research Institute, Toronto, Ontario, Canada.
Jean
J
Gariepy
Université de Montréal, Montréal, Québec.
Rafick-Pierre
RP
Sekaly
Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada. Centre de Recherche sur le Cancer de l'Université Laval, Québec, Canada.
Louis
L
Lacombe
Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada. Centre de Recherche sur le Cancer de l'Université Laval, Québec, Canada.
Yves
Y
Fradet
McMaster University, Hamilton, Ontario, Canada. Hamilton Health Sciences, Hamilton, Ontario, Canada. foleyr@hhsc.ca.
Ronan
R
Foley
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000637:transplantation*; D005240:Feasibility Studies; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D018396:Mucin-1 / Q000276:immunology*; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000276:immunology / Q000628:therapy*; D014611:Vaccination
D019496:Cancer Vaccines; C060192:MUC1 protein, human; D018396:Mucin-1; D017430:Prostate-Specific Antigen