title: Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): study protocol of a phase I/II clinical trial.
abstract: BACKGROUND
  Adenocarcinoma originating from the digestive system is a major contributor to cancer-related deaths worldwide. Tumor recurrence, advanced local growth and metastasis are key factors that frequently prevent these tumors from curative surgical treatment. Preclinical research has demonstrated that the dependency of these tumors on supporting mesenchymal stroma results in susceptibility to cell-based therapies targeting this stroma.
  
  
  METHODS
  TREAT-ME1 is a prospective, uncontrolled, single-arm phase I/II study assessing the safety and efficacy of genetically modified autologous mesenchymal stromal cells (MSC) as delivery vehicles for a cell-based gene therapy for advanced, recurrent or metastatic gastrointestinal or hepatopancreatobiliary adenocarcinoma. Autologous bone marrow will be drawn from each eligible patient after consent for bone marrow donation has been obtained (under a separate EC-approved protocol). In the following ~10 weeks the investigational medicinal product (IMP) is developed for each patient. To this end, the patient's MSCs are stably transfected with a gamma-retroviral, replication-incompetent and self-inactivating (SIN) vector system containing a therapeutic promoter - gene construct that allows for tumor-specific expression of the therapeutic gene. After release of the IMP the patients are enrolled after given informed consent for participation in the TREAT-ME 1 trial. In the phase I part of the study, the safety of the IMP is tested in six patients by three treatment cycles consisting of re-transfusion of MSCs at different concentrations followed by administration of the prodrug Ganciclovir. In the phase II part of the study, sixteen patients will be enrolled receiving IMP treatment. A subgroup of patients that qualifies for surgery will be treated preoperatively with the IMP to verify homing of the MSCs to tumors as to be confirmed in the surgical specimen.
  
  
  CONCLUSIONS
  The TREAT-ME1 clinical study involves a highly innovative therapeutic strategy combining cell and gene therapy and is conducted at a high level of pharmaceutical quality ensuring patient safety. This patient-tailored approach represents the first clinical study worldwide utilizing genetically engineered MSCs in humans.
  
  
  BACKGROUND
  EU Clinical Trials Register/European Union Drug Regulating Authorities Clinical Trials Database number: 2012-003741-15.
authors: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany. hanno.niess@med.uni-muenchen.de.
authors: Hanno
authors: H
authors: Niess
authors: Department of Medical Oncology and Comprehensive Cancer Center, Hospital of the University of Munich, Munich, Germany. jobst.von-einem@med.uni-muenchen.de.
authors: Jobst C
authors: JC
authors: von Einem
authors: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany. michael.thomas@med.uni-muenchen.de.
authors: Michael N
authors: MN
authors: Thomas
authors: Department of Medical Oncology and Comprehensive Cancer Center, Hospital of the University of Munich, Munich, Germany. marlies.michl@med.uni-muenchen.de.
authors: Marlies
authors: M
authors: Michl
authors: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany. martin.angele@med.uni-muenchen.de.
authors: Martin K
authors: MK
authors: Angele
authors: Apceth GmbH and Co. KG, Munich, Germany. r.huss@apceth.com.
authors: Ralf
authors: R
authors: Huss
authors: Apceth GmbH and Co. KG, Munich, Germany. c.guenther@apceth.com.
authors: Christine
authors: C
authors: Günther
authors: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universitaet Muenchen, Arbeitsgruppe Klinische Biochemie, Munich, Germany. peter.nelson@med.uni-muenchen.de.
authors: Peter J
authors: PJ
authors: Nelson
authors: Department of Surgery, Hospital of the University of Magdeburg, Magdeburg, Germany. christiane.bruns@med.ovgu.de.
authors: Christiane J
authors: CJ
authors: Bruns
authors: Department of Medical Oncology and Comprehensive Cancer Center, Hospital of the University of Munich, Munich, Germany. volker.heinemann@med.uni-muenchen.de.
authors: Volker
authors: V
authors: Heinemann
mesh_terms: D006801:Humans; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D015870:Gene Expression; D023061:Gene Order; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D012107:Research Design