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Research Area 1: Targeted cellular therapy

Projects A, B, C

Immunopharmacology Group, Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Universität München

Heads: Prof. Dr. Sebastian Kobold and Prof. Dr. Stefan Endres

Contact: sebastian.kobold(at)med.uni-muenchen.de

 

Goals and research areas

  1. Enhancement of T cell-based therapy through retroviral modification of T cells with the aim of a) increase tumor infiltration, b) protect T cells from immune suppression and c) increase tumor cell recognition
  2. Antibody-based therapy of tumors. We work both on new target structures and on new antibody derivatives
  3. Use of Toll-like-receptor-7 (TLR7) agonists for cancer immunotherapy. New TLR7 agonists are used to empower innate immune responses against tumors
  4. Role of interleukin-22 in tumorigenesis, progression and therapy resistance

 

Methods

Our group uses a wide range of immunological and molecular biology-based techniques. We are specialized in the preclinical testing of new anti-tumor therapies in relevant in vitro and in vivo models. Our group has access to state-of-the-art devices such as multicolor-flow cytometry, confocal microscopy, cell sorter and next generation sequencing

 

Projects within i-Target

  • Project A: Targeting of tumor-associated immune cells through novel fusion proteins

    Brief description: We will engineer primary murine and human T cells with different receptors targeting different immune cell compartments. The project encompasses in vivo animal experiments, in vitro T cell engineering and functional assays, as well as work with human and patient material.

  • Project B: Harnessing memory NK cells for cancer treatment

    Brief description: We will develop and apply established protocols for the induction of NK-specific immunity against cancer. The project will cover in vitro and in vivo techniques using state-of-the-art methods.

  • Project C: Targeting tumor-promoting inflammation through recombinant proteins

    Brief description: Based on the importance of inflammation for cancer treatment and progression, we will utilize and target different actors to regulate tumor-driving inflammation. This project will involve recombinant techniques as well as in vitro and in vivo characterization.

 

Selected publications

  1. Kobold S, Steffen J, Grassmann S, Henkel J, Castoldi R, Zeng Y, Schmollinger JC, Schnurr M, Rothenfußer S, Sustmann C, Niederfellner G, Klein C, Bourquin C and Endres S: and Endres S:

    A new bispecific T cell recruiting antibody enhances anti-tumor activity of adoptive T cell transfer

    Journal of the National Cancer Institute 2015; 107(1): 364

  2. Kobold S, Grassmann S, Chaloupka M, Lampert C, Wenk S, Kraus F, Rapp M, Düwell P, Zeng Y, Schmollinger JC, Schnurr M, Endres S and Rothenfußer S:

    A new fusion receptor overcomes PD-1-mediated immunosuppression in adoptive T cell therapy.

    Journal of the National Cancer Institute 2015; 107 (8)

  3. Rapp M, Grassmann S, Chaloupka M, Layritz P, Kruger S, Ormanns S, Jansen KP, Endres S, Anz D and Kobold S:

    C-C chemokine receptor type 4 transduction of T cells enhances interaction with dendritic cells, tumor infiltration and therapeutic efficacy of adoptive T cell transfer.

    Oncoimmunology 2016, 5(3)   

  4. Wiedemann GM, Jacobi SJ, Chaloupka M, Hamm S, Strobl S, Baumgartner R, Rothenfusser S, Duewell P, Endres S and Kobold S: 

    A novel TLR7 agonist reverses NK cell anergy and cures lymphoma-bearing mice.

    Oncoimmunology 2016, 5(7)   

  5. Voigt C, May P, Gottschlich A, Markota A, Wenk D, Gerlach I, Voigt S, Stathopoulos GT, Arendt KAM, Heise C, Rataj F, Janssen KP, Königshoff M, Winter H, Himsl I, Thasler WE, Schnurr M, Rothenfußer S, Endres S, Kobold S:

    Cancer cells induce interleukin-22 production from memory CD4+ T cells via interleukin-1 to promote tumor growth.

    Proceedings of the National Academy of Science USA 2017, 114 (49)

     

    Project D

    Immunotherapy Group, Department of Internal Medicine III, Klinikum der Universität München

    Head: Prof. Dr. Marion Subklewe

    Contact: marion.subklewe(at)med.uni-muenchen.de

    Ziele und Arbeitsgebiete

    1. Zelluläre Immuntherapie mittels Dendritischer Zellen
    Seit 01/2014 aktiv rekrutierende „Proof of concept“ Phase I / II Studie  mit RNA-transfizierten dendritischen Zellen in der Postremissiontherapie von Patienten mit Akuter Myeloischer Leukämie 

    2. Entwicklung von multispezifischen Antikörpern zur Rekrutierung von T- und NK-Zellen.
    Die Expression von Oberflächenmolekülen als geeignete Targetstrukturen für eine Antikörper-basierte Immuntherapie wird auf Zelllininen und Primärmaterial geprüft und funktionelle Daten  zur Effektivität der bi- und multispezifischen Antikörper vermittelten Zelllyse überprüft

    3. Immunmodulation
    Der Fokus liegt auf der Untersuchung von Zelloberflächenmolekülen und immunregulatorischen Zelltypen bei Patienten mit AML.

     

    Methoden

    Die AG Immuntherapie hat ihren Fokus im Bereich der zellbiologischen und immunologischen Methoden. Die Arbeitsgruppe ist spezialisiert in der präklinischen Testung von Therapiekonzepten in relevanten in vitro Modellen. Die Arbeitsgruppe hat Zugang zu state-of-the-art apparativer Ausstattung wie 7-Farbendurchflusszytometrie, konfokale Mikroskopie, Zellsorter, Elispot und molekulargenetischen Methoden einschließlich next generation sequencing. Es bestehen enge Kollaboration zu molekulargenetischen und proteinbiochemischen Arbeitsgruppen (Helmholtz Zentrum, Genzentrum).

     

    Projects within i-Target

    Project D: Therapeutic vaccines and immune check point blockade in leukemia

    Brief description: We have documented the generation of superior dendritic cells (DCs) from monocytes of AML patients using a fast, TLR ligand-containing maturation cocktail. Based on our preclinical data, we have initiated a proof-of-concept trial using RNA-transfected DCs for postremission therapy in AML. Therapeutic vaccinations induced cellular immune responses may be hampered by upregulation of immune inhibitory molecules (“immune checkpoint markers”) on target cells.

    The aim of this Ph.D. project is to identify immuninhibitory pathways relevant in AML as mechanisms of immune escape and as therapeutic targets. The therapeutic potential of checkpoint inhibitors and other immunmodulatory drugs will be assessed in vitro and in collaboration also in an in vivo AML mouse model. The methods will comprise a wide range of cellular and immunological methods and will optionally include in vivo experiments.

    Selected Publications

    1. Krupka C, Kufer P, Kischel R, Zugmaier G, Bögeholz J, Köhnke T, Lichtenegger FS, Schneider S, Metzeler KH, Fiegl M, Spiekermann K, Baeuerle PA, Hiddemann W, Riethmüller G, Subklewe M.:
      CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330

      Blood. 2014 Jan 16;123(3)

    2. Huang Y, Wolf S, Beck B, Köhler LM, Khoury K, Popowicz GM, Goda SK, Subklewe M, Twarda A, Holak TA, Dömling A.:
      Discovery of highly potent p63-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities.

      ACS Chem Biol. 2014 Mar 21;9(3):802-11.

    3. Anger A, Amache JP, Berninghausen O, Habeck M, Subklewe M, Wilson D, Beckmann R:
      Structures of the human and Drosophila 80S ribosome.

      Nature 2013; May; 497: 80-85.

    4. Lichtenegger F, Mueller K, Otte B, Beck B, Hiddemann W, Schendel DJ, Subklewe M:

      CD86 and IL-12p70 Are Key Players for T Helper 1 Polarization and Natural Killer Cell Activation by Toll-Like Receptor-Induced Dendritic Cells.

      PLoS One 2012; Sep 4.

    5. Beck B, Dörfel D, Lichtenegger FS, Geiger C, Lindner L, Merk M, Schendel DJ, Subklewe M:

      Effects of TLR agonists on maturation and function of 3-day dendritic cells from AML patients in complete remision.

      J Translational Medicine 2011; Sep 13;9:151.

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