DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8+ T-cell responses and increases PSA doubling time

Abstract

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), PSMA27–35. 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 PSMA27-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 PSMA27-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-PSMA27 vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-012-1270-0) contains supplementary material, which is available to authorized users.

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

“…This method leads to the formation of transient pores, which increases the uptake of pDNA by cells [114][115][116][117]. Some of these devices have already been tested in the clinic [118,119]. -Magnetic transfection efficacy was 350-fold as compared to conventional transfection as shown in experiments delivering the luciferase reporter gene to target cells.…”

Wilms’ tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)

“…57,58 This allowed us to undertake a 'start/stop' evaluation once 12 patients had been enrolled into each vaccination group of the study and had been evaluated to 6 months (molecular monitoring). An interim analysis of these CML patients' molecular data (BCR-ABL and WT1) was to be carried out including up to 6 months of data.…”

Harnessing DNA-induced immune responses for improving cancer vaccines

“…131,132 A recent clinical trial using DNA electroporation in patients with prostate cancer showed enhanced humoral and CD8 + T cell responses against prostate cancer compared with DNA vaccine alone. 104,133 Another study showed increased immunogenicity of an HIV-1 DNA vaccine injected intramuscularly followed by electroporation in healthy volunteers. 48 Employing electroporation directly following may have an impact on DNA vaccine trials.…”

“…48 Employing electroporation directly following may have an impact on DNA vaccine trials. Chudley et al have shown that intramuscular injection followed by electroporation resulted in increased specific CTL response, 133 and outcomes from other clinical trials utilizing electroporation are eagerly awaited. Although most of the studies have been conducted using intramuscular delivery, intradermal electroporation with plasmids encoding tumor antigens has shown to be highly efficient in inducing specific CD8 + T cell responses and conferring protection against tumors in mouse models.…”