NCT Research

CCRP Colorectal

Summary

The program has developed a strong focus on integrated analytical pipelines and translational projects. Multidisciplinary treatment concepts and innovative clinical trials include MARACON, LUMINESCENCE, Vaxxim, and ATACC. Individual diagnostic and analytic procedures for patients include comprehensive immunological workup as well as precision medicine molecular tumor boards. In addition, strong epidemiological cohorts (DACHS, BLITZ, Gekko) support further NCT research projects. A DFG-funded clinical research unit (KFO 227) was recently successfully completed, delineating key mechanisms of CRC metastasis and produced translational clinical concepts. Intensive collaborations between all involved departments allow an integrated clinical as well as preclinical workflow.

CCRP Colorectal
 

Members designated as Contact Person

PD Dr. Grüllich
Medical Oncology

 
 
 

Prof. Dr. Dirk Jäger
Dept. of Medical Oncology, NCT/Heidelberg University Hospital

PD Dr. Carsten Grüllich

Dept. of Medical Oncology, NCT/Heidelberg University Hospital

Dr. Niels Halama
Dept. of Medical Oncology, NCT/Heidelberg University Hospital

Dr. Bruno C. Köhler

Dept. of Medical Oncology, NCT/Heidelberg University Hospital

Prof. Dr. Ronald Koschny
Dept. of Gastroenterology, Infectious Diseases, Intoxication, Heidelberg University Hospital

Dr. Jan Pfeiffenberger
Dept. of Gastroenterology, Infectious Diseases, Intoxication, Heidelberg University Hospital

Prof. Dr. Martin Schneider

Dept. of General, Visceral and Transplantation Surgery, Heidelberg University Hospital

Prof. Dr. Wolfgang Stremmel

Dept. of Gastroenterology, Infectious Diseases, Intoxication, Heidelberg University Hospital

Prof. Dr. Alexis Ulrich
Dept. of General, Visceral and Transplantation Surgery, Heidelberg University Hospital

  • Molecular basis of CRC growth, invasion, metastases and resistance (e.g., KFO 227 (Klinische Forschergruppe/Clinical Research Group))
  • Systematic characterization of tumor–host immune interactions.
  • Elucidate functional and genetic heterogeneity of tumor initiating cells and develop therapeutic targets.
  • Development of novel immunotherapeutic approaches for colorectal cancer.
  • Development of novel therapeutic constructs.
  • Identify molecular markers for prevention and early detection.
  • Translation of novel predictive and prognostic markers into diagnostic assays.
  1. N. Halama, I. Zoernig, A. Berthel, C. Kahlert, F. Klupp, M. Suarez-Carmona, T. Suetterlin, K. Brand, J. Krauss, F. Lasitschka, T. Lerchl, C. Luckner-Minden, A. Ulrich, M. Koch, J. Weitz, M. Schneider, M. W. Buechler, L. Zitvogel, T. Herrmann, A. Benner, C. Kunz, S. Luecke, C. Springfeld, N. Grabe, C. S. Falk and D. Jaeger. Tumoral immune cell exploitation in colorectal cancer liver metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell, Cancer Cell. 29(4):587-601 (2016)
  2. Berthel A, Zoernig I, Valous NA, Kahlert C, Klupp F, Ulrich A, Weitz J, Jaeger D, Halama N. Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival. Oncoimmunology. 2017
  3. Reissfelder C, Stamova S, Gossmann C, Braun M, Bonertz A, Walliczek U, Grimm M, Rahbari NN, Koch M, Saadati M, Benner A, Büchler MW, Jäger D, Halama N, Khazaie K, Weitz J, Beckhove P. Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis. J Clin Invest. 2015
  4. Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schäkel K, Garbi N, Jäger D, Weitz J, Schmitz-Winnenthal H, Hämmerling GJ, Beckhove P. Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013
  5. Kahlert C, Pecqueux M, Halama N, Dienemann H, Muley T, Pfannschmidt J, Lasitschka F, Klupp F, Schmidt T, Rahbari N, Reissfelder C, Kunz C, Benner A, Falk C, Weitz J, Koch M. Tumour-site-dependent expression profile of angiogenic factors in tumour-associated stroma of primary colorectal cancer and metastases. Br J Cancer. 2014
  6. Anna-Lena Scherr, Georg Gdynia, Mariam Salou, Praveen Radhakrishnan, Nicole Kautz, Adam Jassowicz, Christin Elssner, Walee Chamulitrat, Dirk Jaeger, Mathias Heikenwalder, Martin Schneider, Achim Weber, Wilfried Roth, Henning Schulze-Bergkamen and Bruno Christian Koehler Bcl-xL is an oncogenic driver in colorectal Cell Death Dis. 2016 Aug 18;7(8):e2342. doi: 10.1038/cddis.2016.233.
  7. Radhakrishnan P, Ruh N, Harnoss JM, Kiss J, Mollenhauer M, Scherr AL, Platzer LK, Schmidt T, Podar K, Opferman JT, Weitz J, Schulze-Bergkamen H, Koehler BC, Ulrich A, Schneider M. Prolyl hydroxylase 3 attenuates MCL-1-mediated ATP production to suppress the metastatic potential of colorectal cancer cells. Cancer Res. 2016 Feb 26. pii: canres.1474.2015
  8. Koehler BC, Scherr AL, Lorenz S, Urbanik T, Kautz N, Elssner C, Welte S, Bermejo JL, Jäger D, Schulze-Bergkamen H. Beyond cell death - antiapoptotic Bcl-2 proteins regulate migration and invasion of colorectal cancer cells in vitro. PLoS One. 2013 Oct 3;8(10):e76446. doi: 10.1371/journal.pone.0076446. eCollection 2013.
  9. Koehler BC, Jassowicz A, Scherr AL, Lorenz S, Radhakrishnan P, Kautz N, Elssner C, Weiss J, Jaeger D, Schneider M, Schulze-Bergkamen H. Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling. BMC Cancer. 2015 Nov 19;15:919. doi: 10.1186/s12885-015-1929-y.

Clinical Activities

Dedicated tumor boards with multidisciplinary teams have been established and allow a seamless integration of patient care. In this setting, the existing partnerships on a scientific level allow rapid generation not only of clinical decisions, but also the development of clinically translational programs. The diagnostic possibilities through scientific developments (circulating tumor cells, angiogenesis, immune cell profiling) also provide cutting-edge diagnostics for better patient stratification. Internationally awarded scientific workflows are being translated into clinical use. Participating partners include not only clinical departments (internal medicine, surgery, pathology), but also come from the fields of immunology and molecular expertise (e.g. bioinformatics).

The in the following described Vaximm (VXM01) trial has been successfully completed and is awaiting further follow-up. Results will also be presented at the DGHO meeting (Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie) in Fall 2017. Additionally, the below described ATACC trial is successfully recruiting patients.

Vaximm (VXM01)
Angiogenesis contributes to solid tumor growth and metastasis. Compounds like bevacizumab and others, for example small molecules such as sunitinib and axitinib that specifically target the tumor neovasculature have shown efficacy in a range of tumor indications. Tumor neovasculature is lined with endothelial cells that are overexpressing vascular endothelial growth factor receptor (VEGFR) 2 and are readily accessible via the blood stream. The genetic stability of those cells and their ability to support hundreds of tumor cells per endothelial cell make them a prime target for anti-cancer therapy, be it via antibodies, tyrosine kinase inhibitors, or vaccines. Recently, T-cell based immunotherapy has gained some clinical success in prostate cancer and validated the potential of anti-cancer vaccination which was often demonstrated preclinically. Activating the immune system against cancer cells faces multiple challenges. For example, cancerous lesions are often polyclonal and cancer cells have the propensity to mutate. Antigen specific therapy often only results in a selection of non-antigen bearing cells. Further hurdles include tumor encapsulation and loss or down-regulation of MHC molecules. Vaccination approaches that target that the tumor neovasculature should in theory overcome those hurdles. The trial presented here attempts to combine anti-angiogenic therapy and vaccination, targeting VEGFR-2 using a new vaccine (VXM01). Hypothetically, vaccination with VXM01 should lead to breakdown of existing tumor vasculature and support the development of an immune memory against proliferating endothelial cells.

ATACC
The study “Phase I trial of Adoptive T cell Therapy with Activated P53 specific T cells for Treatment of Advanced Colorectal Cancer” is an open label, single arm trial. Most patients with colorectal carcinoma (CRC) accumulate high numbers of endogenous tumor antigen specific cytotoxic and helper memory T cells in their blood. Upon appropriate reactivation, tumor antigen specific T cells can recognize and eliminate autologous tumor cells. However, their reactivation within the patients is functionally inhibited by a variety of tumor derived immune suppressive mechanisms and by immune suppressive endogenous regulatory T cells. Appropriate reactivation of endogenous tumor specific T cells can be achieved ex vivo by their stimulation with antigen pulsed autologous dendritic cells in the absence of regulatory T cells. Upon adoptive transfer, specifically reactivated T cells from cancer patients can efficiently reject autologous human tumors in vivo. A major target antigen of anti tumor effector T cells in CRC patients is p53, which is overexpressed in many colorectal cancers. Within this clinical trial, high numbers of endogenous tumor specific T cells will be harvested by leukapheresis from the blood of CRC patients harbouring p53-reactive T cells. Isolated T cells will be depleted from regulatory T cells and specifically reactivated for three days ex vivo with three synthetic long peptides containing the most immunogenic regions of p53 using autologous dendritic cells as antigen presenting cells. Activated T cells will be re-infused into the patients. Practicability and tolerability as well as hints of clinical efficacy of an adoptive transfer of tumor specific ex vivo activated endogenous T cells was previously demonstrated in a pilot study of altogether 16 breast cancer patients.

Preclinical Activities

The development of an integrated pipeline for systematic analyses of the (immunological) microenvironment is a unique expertise within this CCRP, allowing not only preclinical analytic procedures but also subsequent concomitant clinical analyses with human tissue samples. Expansion of this pipeline now led to the incorporation of concomitant peripheral blood analysis (autoantibody-profiling, cytokines, ELISPOT, etc.) and the inclusion of comprehensive metabolomics profiling from biopsies. In addition, the development of a fully human organotypic tumor explant model system confers a decisive advantage, utilizing the competencies of all involved partners for more human-relevant experimental analytic procedures. Trials are upcoming that harness the power of the explant model system. Circulating tumor vesicles & circulating tumor cell profiling and a strong focus on implementation of next-generation sequencing allow cutting-edge analyses of angiogenesis, tumor initiation, and metastatic spreading.

Within the KFO227 (Klinische Forschergruppe/Clinical Research Group), research focuses on the mechanisms leading to the formation of distant metastases from colorectal cancer. Physicians and scientist are closely collaborating to gain a deeper understanding on the complex metastasization process in order to discover new therapeutic strategies. Research from CCRP projects discovered quintessential metabolic mechanisms for cancer cell spread (Radhakrishnan et al., Cancer Res. 2016). Furthermore, we have generated a variety of animal models to study colorectal cancer onset, progression and therapy (e.g. Scherr et al., CDDiss 2016). Comprehensive analyses tools including cutting-edge technologies (e.g. mice colonoscopy) have been established. Biobanking structures including tissue and liquid biopsies have been built up within the infrastructure of the KFO. The collaborative approaches within the framework of the KFO enable researchers to analyze liquid biopsies, tissue samples, and substantial clinical data. Joining forces from basic researchers and clinicians fosters a timed translation of preclinical discoveries into early clinical trials.