Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial.
The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53-SLP) vaccine, twenty patients with recurrent elevation of CA-125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53-SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no > or = grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN-gamma producing p53-specific T-cell responses were induced in all patients who received all 4 immunizations as measured by IFN-gamma ELISPOT. An IFN-gamma secretion assay showed that vaccine-induced p53-specific T-cells were CD4(+), produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53-specific response. P53-specific T-cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53-specific T-cells. As best clinical response, stable disease evaluated by CA-125 levels and CT-scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine-induced immunity. This study shows that the p53-SLP vaccine is safe, well tolerated and induces p53-specific T-cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper-1 polarization and clinical efficacy.
Leffers
Ninke
N
Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Lambeck
Annechien J A
AJ
Gooden
Marloes J M
MJ
Hoogeboom
Baukje-Nynke
BN
Wolf
Rinze
R
Hamming
Ineke E
IE
Hepkema
Bouke G
BG
Willemse
Pax H B
PH
Molmans
Barbara H W
BH
Hollema
Harry
H
Drijfhout
Jan W
JW
Sluiter
Willem J
WJ
Valentijn
A Rob P M
AR
Fathers
Loraine M
LM
Oostendorp
Jaap
J
van der Zee
Ate G J
AG
Melief
Cornelis J
CJ
van der Burg
Sjoerd H
SH
Daemen
Toos
T
Nijman
Hans W
HW
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D002465:Cell Movement; D005260:Female; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008875:Middle Aged; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
D019496:Cancer Vaccines; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma