DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8(+) T-cell responses and increases PSA doubling time.
We report on the immunogenicity and clinical effects in a phase I/II dose escalation trial of a DNA fusion vaccine in patients with prostate cancer. The vaccine encodes a domain (DOM) from fragment C of tetanus toxin linked to an HLA-A2-binding epitope from prostate-specific membrane antigen (PSMA), PSMA(27-35). We evaluated the effect of intramuscular vaccination without or with electroporation (EP) on vaccine potency. Thirty-two HLA-A2(+) patients were vaccinated and monitored for immune and clinical responses for a follow-up period of 72 weeks. At week 24, cross-over to the immunologically more effective delivery modality was permitted; this was shown to be with EP based on early antibody data, and subsequently, 13/15 patients crossed to the +EP arm. Thirty-two HLA-A2(-) control patients were assessed for time to next treatment and overall survival. Vaccination was safe and well tolerated. The vaccine induced DOM-specific CD4(+) and PSMA(27)-specific CD8(+) T cells, which were detectable at significant levels above baseline at the end of the study (p = 0.0223 and p = 0.00248, respectively). Of 30 patients, 29 had a measurable CD4(+) T-cell response and PSMA(27)-specific CD8(+) T cells were detected in 16/30 patients, with or without EP. At week 24, before cross-over, both delivery methods led to increased CD4(+) and CD8(+) vaccine-specific T cells with a trend to a greater effect with EP. PSA doubling time increased significantly from 11.97 months pre-treatment to 16.82 months over the 72-week follow-up (p = 0.0417), with no clear differential effect of EP. The high frequency of immunological responses to DOM-PSMA(27) vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing.
Experimental Cancer Medicine Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK.
Lindsey
L
Chudley
Katy
K
McCann
Ann
A
Mander
Torunn
T
Tjelle
Juan
J
Campos-Perez
Rosemary
R
Godeseth
Antonia
A
Creak
James
J
Dobbyn
Bernadette
B
Johnson
Paul
P
Bass
Catherine
C
Heath
Paul
P
Kerr
Iacob
I
Mathiesen
David
D
Dearnaley
Freda
F
Stevenson
Christian
C
Ottensmeier
D000368:Aged; D000369:Aged, 80 and over; D000954:Antigens, Surface / Q000627:therapeutic use*; D019677:Artificial Gene Fusion; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D018274:Electroporation; D043425:Glutamate Carboxypeptidase II / Q000627:therapeutic use*; D015789:HLA-A2 Antigen / Q000032:analysis; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D013744:Tetanus Toxin / Q000627:therapeutic use*; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology
D000954:Antigens, Surface; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D013744:Tetanus Toxin; D019444:Vaccines, DNA; C040635:tetanus toxin fragment C; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen