Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): study protocol of a phase I/II clinical trial

BMC Cancer

Hanno Niess⁵  Jobst C von Einem¹  Michael N Thomas⁵  Marlies Michl¹  Martin K Angele⁵  Ralf Huss³  Christine Günther³  Peter J Nelson⁴  Christiane J Bruns²  Volker Heinemann¹ 

[1] Department of Medical Oncology and Comprehensive Cancer Center, Hospital of the University of Munich, Munich, Germany

[2] Department of Surgery, Hospital of the University of Magdeburg, Magdeburg, Germany

[3] Apceth GmbH and Co. KG, Munich, Germany

[4] Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universitaet Muenchen, Arbeitsgruppe Klinische Biochemie, Munich, Germany

[5] Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany

关键词: Ganciclovir;    HSV-Tk;    Clinical trial;    Suicide gene therapy;    Cell therapy;    Gene therapy;    MSC;    Genetically engineered mesenchymal stromal cells;   

Others  :  1161217
DOI  :  10.1186/s12885-015-1241-x

 received in 2014-09-30, accepted in 2015-03-20,  发布年份 2015

【 摘 要 】

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/Design

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.

Discussion

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.

Trial registration

EU Clinical Trials Register/European Union Drug Regulating Authorities Clinical Trials Database number: 2012-003741-15

【 授权许可】

   
2015 Niess et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Siegel R, Ma J, Zou Z, Jemal A: Cancer statistics, 2014. CA Cancer J Clin 2014, 64(1):9-29.
• [2]Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100(1):57-70.
• [3]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144(5):646-74.
• [4]Hofmeister V, Schrama D, Becker JC: Anti-cancer therapies targeting the tumor stroma. Cancer Immunol Immunother: CII 2008, 57(1):1-17.
• [5]Reagan MR, Kaplan DL: Concise review: Mesenchymal stem cell tumor-homing: detection methods in disease model systems. Stem Cells 2011, 29(6):920-7.
• [6]Xin H, Sun R, Kanehira M, Takahata T, Itoh J, Mizuguchi H, et al.: Intratracheal delivery of CX3CL1-expressing mesenchymal stem cells to multiple lung tumors. Mol Med 2009, 15(9–10):321-7.
• [7]Loebinger MR, Eddaoudi A, Davies D, Janes SM: Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res 2009, 69(10):4134-42.
• [8]Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M: Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002, 62(13):3603-8.
• [9]Conrad C, Husemann Y, Niess H, von Luettichau I, Huss R, Bauer C, et al.: Linking transgene expression of engineered mesenchymal stem cells and angiopoietin-1-induced differentiation to target cancer angiogenesis. Ann Surg 2011, 253(3):566-71.
• [10]Niess H, Bao Q, Conrad C, Zischek C, Notohamiprodjo M, Schwab F, et al.: Selective targeting of genetically engineered mesenchymal stem cells to tumor stroma microenvironments using tissue-specific suicide gene expression suppresses growth of hepatocellular carcinoma. Ann Surg 2011, 254(5):767-74. discussion 774–775
• [11]Zischek C, Niess H, Ischenko I, Conrad C, Huss R, Jauch KW, et al.: Targeting tumor stroma using engineered mesenchymal stem cells reduces the growth of pancreatic carcinoma. Ann Surg 2009, 250(5):747-53.
• [12]Hamel W, Magnelli L, Chiarugi VP, Israel MA: Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res 1996, 56(12):2697-702.
• [13]Freytag SO, Stricker H, Pegg J, Paielli D, Pradhan DG, Peabody J, et al.: Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res 2003, 63(21):7497-506.
• [14]Freytag SO, Stricker H, Peabody J, Pegg J, Paielli D, Movsas B, et al.: Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer. Mol Ther 2007, 15(3):636-42.
• [15]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al.: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8(4):315-7.
• [16]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228-47.
• [17]Loew R, Meyer Y, Kuehlcke K, Gama-Norton L, Wirth D, Hauser H, et al.: A new PG13-based packaging cell line for stable production of clinical-grade self-inactivating gamma-retroviral vectors using targeted integration. Gene Ther 2010, 17(2):272-80.
• [18]Schilz AJ, Kuhlcke K, Fauser AA, Eckert HG: Optimization of retroviral vector generation for clinical application. J Gene Med 2001, 3(5):427-36.
• [19]Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al.: The european organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993, 85(5):365-76.
• [20]Hjermstad MJ, Fossa SD, Bjordal K, Kaasa S: Test/retest study of the european organization for research and treatment of cancer core quality-of-life questionnaire. J Clin Oncol 1995, 13(5):1249-54.
• [21]Bao Q, Zhao Y, Niess H, Conrad C, Schwarz B, Jauch KW, et al.: Mesenchymal stem cell-based tumor-targeted gene therapy in gastrointestinal cancer. Stem Cells Dev 2012, 21(13):2355-63.
• [22]CHMP/GTWP/125459/06 Non-clinical studies required before first clinical use of gene therapy medicinal products [http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003942.pdf].
• [23]EMEA/CHMP/GTWP/60436/2007 Guideline on follow-up of patients administered with gene therapy medicinal products [http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/11/WC500013424.pdf].