Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer

Abstract

BackgroundThe investigational oral DNA vaccine VXM01 targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and uses Salmonella typhi Ty21a as a vector. The immune reaction elicited by VXM01 is expected to disrupt the tumor neovasculature and, consequently, inhibit tumor growth. VXM01 potentially combines the advantages of anti-angiogenic therapy and active immunotherapy.Methods/DesignThis phase I trial examines the safety, tolerability, and immunological and clinical responses to VXM01. The randomized, placebo-controlled, double blind dose-escalation study includes up to 45 patients with locally advanced and stage IV pancreatic cancer. The patients will receive four doses of VXM01 or placebo in addition to gemcitabine as standard of care. Doses from 106 cfu up to 1010 cfu of VXM01 will be evaluated in the study. An independent data safety monitoring board (DSMB) will be involved in the dose-escalation decisions. In addition to safety as primary endpoint, the VXM01-specific immune reaction, as well as clinical response parameters will be evaluated.DiscussionThe results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine VXM01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications.Trial registrationEudraCT No.: 2011-000222-29, NCT01486329, ISRCTN68809279

Vaccination approach to anti-angiogenic treatment of cancer

“…Importantly, although vaccination did not interfere with fertility of female mice, wound healing was significantly delayed in vaccinated mice. Currently, a humanized version of this VEGFR2 vaccine is investigated in a phase I clinical trial in patients with advanced pancreatic cancer [86]. Considering the observations made in the pre-clinical phase, it will be crucial to monitor adverse events intensely.…”

Trial watch

“…In particular, the oral administration of bacterial vectors has only been tested in a cohort of pancreatic cancer patients (TAA: vascular endothelial growth factor receptor 2, VEGFR2); 121 , 179 adenoviral or poxviral vectors (given i.m. or s.c.) have been evaluated in cohorts of non-small cell lung carcinoma (NSCLC) patients (TAA: L523S), 180 melanoma patients (TAA: multiple epitopes from distinct melanoma antigens) 150 , 181 and prostate carcinoma patients (TAAs: prostate-specific membrane antigen, PSMA); 182 , 183 and biodegradable polymeric materials have been tested in cohorts of anal dysplasia patients (TAA: HPV-16 E7), 184 CIN patients (TAAs: HPV-16 E6/E7) 185 and individuals bearing advanced solid tumors (TAA: cytochrome P450 1B1) 186 .…”

“…Five of these studies are based on bacterial vectors, as (1) four are testing a live attenuated variant of Listeria monocytogenes engineered to express E7 from HPV-16 (ADXS11-001), 187 delivered i.v. either as a standalone intervention to individuals affected by grade 2/3 CIN (NCT01116245), persistent/recurrent cervical carcinoma (NCT01266460) and oropharyngeal cancer (NCT01598792), or in combination with 5-fluorouracil, mitomycin and intensity-modulated radiation therapy to anal carcinoma patients (NCT01671488); and (2) one is assessing the safety and efficacy of an attenuated strain of Salmonella typhimurium encoding VEGFR2 (VXM01), 121 , 179 administered p.o. to patients affected by locally advanced, inoperable Stage IV pancreatic cancer (NCT01486329).…”

“…Finally, although increased transfection efficiencies as achieved with electroporation elevate the risk of (potentially oncogenic) integration, this appears to remain within acceptable levels 133 . As it stands, electroporation constitutes the delivery method for DNA vaccines best suited for clinical applications; though ever more encouraging results are being obtained with preparation that exploit the oral route, including bacterial and eukaryotic vectors 121 , 134 …”

Trial watch: Naked and vectored DNA-based anticancer vaccines

“…First, they are compatible with oral administration. [40][41][42] Second, they both have been shown to elicit potent mucosal immune responses, [43][44][45] which are superior to intramuscular ones, possibly owing to endogenous immunostimulatory factors that trigger Toll-like receptor (TLR) signaling (such as bacterial lipopolysaccharide). [46][47][48][49][50] As an alternative to electroporation, DNA-based vaccines can be delivered via the transdermal route, by gene gun, 51,52 jet injection, 53,54 and tattooing.…”