title: Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial.
abstract: VEGFR-2 is expressed on tumor vasculature and a target for anti-angiogenic intervention. VXM01 is a first in kind orally applied tumor vaccine based on live, attenuated Salmonella bacteria carrying an expression plasmid, encoding VEGFR-2. We here studied the safety, tolerability, T effector (Teff), T regulatory (Treg) and humoral responses to VEGFR2 and anti-angiogenic effects in advanced pancreatic cancer patients in a randomized, dose escalation phase I clinical trial. Results of the first 3 mo observation period are reported. Locally advanced or metastatic, pancreatic cancer patients were enrolled. In five escalating dose groups, 30 patients received VXM01 and 15 placebo on days 1, 3, 5, and 7. Treatment was well tolerated at all dose levels. No dose-limiting toxicities were observed. Salmonella excretion and salmonella-specific humoral immune responses occurred in the two highest dose groups. VEGFR2 specific Teff, but not Treg responses were overall increased in vaccinated patients. We furthermore observed a significant reduction of tumor perfusion after 38 d in vaccinated patients together with increased levels of serum biomarkers indicative of anti-angiogenic activity, VEGF-A, and collagen IV. Vaccine specific Teff responses significantly correlated with reductions of tumor perfusion and high levels of preexisting VEGFR2-specific Teff while those showing no antiangiogenic activity had low levels of preexisting VEGFR2 specific Teff, showed a transient early increase of VEGFR2-specific Treg and reduced levels of VEGFR2-specific Teff at later time points - pointing to the possibility that early anti-angiogenic activity might be based at least in part on specific reactivation of preexisting memory T cells.
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Friedrich H
authors.initials: FH
authors.lastname: Schmitz-Winnenthal
authors.affiliation: Clinical Pharmacology and Pharmacoepidemiology; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hohmann
authors.affiliation: VAXIMM AG ; Basel, Switzerland.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Niethammer
authors.affiliation: Diagnostic and Interventional Radiology; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Friedrich
authors.affiliation: VAXIMM GmbH ; Mannheim, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Lubenau
authors.affiliation: VAXIMM GmbH ; Mannheim, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Springer
authors.affiliation: VAXIMM AG ; Basel, Switzerland.
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Breiner
authors.affiliation: Clinical Pharmacology and Pharmacoepidemiology; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Ulrich
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Buechler
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Pianka
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Ulla
authors.initials: U
authors.lastname: Klaiber
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Diener
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Leowardi
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schimmack
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Leila
authors.initials: L
authors.lastname: Sisic
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Anne-Valerie
authors.initials: AV
authors.lastname: Keller
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Ruhan
authors.initials: R
authors.lastname: Koc
authors.affiliation: Medical Oncology; National Center for Tumor Diseases ; Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Springfeld
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Knebel
authors.affiliation: General, Visceral and Transplantation Surgery; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Translational Immunology; National Center for Tumor Diseases ; Heidelberg, Germany.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Translational Immunology; National Center for Tumor Diseases ; Heidelberg, Germany.
authors.forename: Mariana
authors.initials: M
authors.lastname: Bucur
authors.affiliation: Translational Immunology; National Center for Tumor Diseases ; Heidelberg, Germany.
authors.forename: Slava
authors.initials: S
authors.lastname: Stamova
authors.affiliation: Translational Immunology; National Center for Tumor Diseases ; Heidelberg, Germany.
authors.forename: Lilli
authors.initials: L
authors.lastname: Podola
authors.affiliation: Clinical Pharmacology and Pharmacoepidemiology; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.affiliation: Diagnostic and Interventional Radiology; University Clinics of Heidelberg ; Heidelberg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Grenacher
authors.affiliation: Translational Immunology; National Center for Tumor Diseases ; Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
keywords: VEGFR2; anti-angiogenic treatment; cancer immunotherapy; oral vaccination; pancreatic cancer