Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma.
BACKGROUND
Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer.


METHODS
Autologous DC of HLA-A*0201(+) patients with hormone-refractory prostate cancer were loaded with antigenic peptides derived from prostate stem cell antigen (PSCA(14-22)), prostatic acid phosphatase (PAP(299-307)), prostate-specific membrane antigen (PSMA(4-12)), and prostate-specific antigen (PSA(154-163)). DC were intradermally applied six times at biweekly intervals followed-in the case of an enhanced immune response-by monthly booster injections. Immune monitoring during the time of ongoing vaccinations (12-59 weeks) included ex vivo ELISPOT measurements, MHC tetramer analysis and in vitro cytotoxicity assays.


RESULTS
Of the initial six patients, three qualified for long-term multi-epitope DC vaccination. This regime was tolerated well by all three patients. The vaccination elicited significant cytotoxic T cell responses against all prostate-specific antigens tested. In addition, memory T cell responses against the control peptides derived from influenza matrix protein and tetanus toxoid were efficiently boosted. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time.


CONCLUSIONS
DC-based multi-epitope immunotherapy with repeated boosting in men with hormone-refractory prostate carcinoma is feasible and generates efficient cellular antitumor responses.
Waeckerle-Men
Ying
Y
Research Department, Cantonal Hospital St. Gallen, 9007, St. Gallen, Switzerland.
Uetz-von Allmen
Edith
E
Fopp
Markus
M
von Moos
Roger
R
Böhme
Christel
C
Schmid
Hans-Peter
HP
Ackermann
Daniel
D
Cerny
Thomas
T
Ludewig
Burkhard
B
Groettrup
Marcus
M
Gillessen
Silke
S
D000135:Acid Phosphatase; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D058851:GPI-Linked Proteins; D043425:Glutamate Carboxypeptidase II / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D017430:Prostate-Specific Antigen / Q000276:immunology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D017027:Protein Tyrosine Phosphatases / Q000276:immunology
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D019496:Cancer Vaccines; D058851:GPI-Linked Proteins; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen