3090 Background: VXM01 is an orally available, bacterially transmitted DNA vaccine targeting VEGFR-2. Pre-clinically, VXM01 showed anti-tumor activity in multiple tumor types. This first-in-human study was designed to evaluate the safety and tolerability of VXM01. Secondary endpoints included VEGFR-2 specific T-cell responses, tumor perfusion changes, and related biomarkers. Methods: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 45 patients with advanced pancreatic cancer. VXM01 or placebo was given on days 1, 3, 5, and 7. Doses were escalated from 10(6) CFU to 10(10) CFU over 5 dose groups, each including 6 VXM01 and 3 placebo patients. VEGFR-2 specific T-cell activity was monitored by ELISpot and T(reg) specificity assays before, during and after the vaccination course. Tumor perfusion was assessed by DCE-MRI on days 0 and 38. Biomarkers included CA19-9, VEGF-A and collagen IV. Results: Patients were enrolled from 12/2011 to 10/2012. Most commonly observed AEs were leukopenia, abdominal pain, and diarrhea, which were all equally distributed between treatment and placebo group. While a mild elevation in average blood pressure was observed in the VXM01 group over the placebo group, the hypertension adverse event rate did not differ between both groups. No DLTs were observed. VEGFR-2 specific effector T-cell response was increased in 57% of evaluable VXM01 treated patients, during and after the vaccination course. In 25% of the VXM01 group, the T-cell response score post-vaccination was higher than maximum placebo levels. In contrast, VEGFR-2 specific T(reg) responses were overall reduced in vaccinated patients. DCE-MRI data indicated a >33% drop in K(trans)/tumor perfusion in 35% of evaluable VXM01 treated patients vs. 10% in the placebo group. Mean changes were -4% (VXM01) and +15% (placebo). Reduced tumor perfusion correlated with VEGFR-2 specific T-cell responses and biomarker responses. Conclusions: VXM01 appeared safe and was well tolerated without DLTs across 5 tested dose levels. The data suggest further that VXM01 induces and enhances a VEGFR-2 specific T-cell response and impacts tumor perfusion. Clinical trial information: ISRCTN68809279.
GV1001 immunotherapy ameliorates joint inflammation in a murine model of rheumatoid arthritis by modifying collagen-specific T-cell responses and downregulating antigen-presenting cells