PD Dr. Uta Höpken

Priv. Doz. Dr. Uta E. Höpken, Research Group Leader
Max-Delbrück Center for Molecular Medicine (MDC)
Robert-Rössle-Str. 10
13125 Berlin
Tel: +49 30 9406 3330
E-Mail: uhoepken(at)mdc-berlin.de
https://www.mdc-berlin.de

Charité - University Medicine Berlin
Lecturer / Privatdozentin
E-Mail: uta.hoepken(at)charite.de

Scientific Scope

Hematological Malignancies and its Immunotherapeutic Targeting

Our group elucidates tumor-stroma interactions in hematological diseases and defines growth- and survival niches for B cell leukemia/lymphoma. By combining pre-clinical mouse models, in vivo imaging, cellular and molecular biology techniques as well as gene expression profiling substantial insight into the complex and dynamic network of tumor cells and the benign infrastructure within lymphatic tissues has been obtained. Targeting the stromal environment is an interesting therapeutic option because this benign compartment is subject to low selective pressure for genetic mutations compared with the tumor cells themselves.

Secondly, we developed Chimeric Antigen Receptor (CAR) T cells for the treatment of B cell disorders, such as a neoplastic diseases of plasma cells and mature B cells, in particular multiple myeloma (MM) or non-Hodgkin’s lymphomas (B-NHLs). Recent demonstration of disease regression of lymphoma by CD19-specific T cells has vitalized adoptive T cell therapy in the scientific community. We already succeeded to develop CAR-T cells that will allow treatment of lymphoid tumors that carry B cell differentation antigens. Examples include i) anti-tumor activity in the treatment of MM, ii) anti-plasma cell activity in dysregulated B cell responses during autoimmunity, and iii) anti-tumor activity in the treatment of mature B-NHLs.

Figure 1: Strategies of next generation CAR-T cells to overcome the hostile tumor microenvironment (Höpken & Rehm, Trends in Cancer 2019). Trafficking of CAR-T cells to the tumor niche is facilitated mainly through expression of chemokine receptors (CCR4, CCR2b) by the CAR-T cells and expression of their respective ligands, chemokines, by the vasculature and by stromal cell networks. CAR-T cells expressing HPSE (heparanase), or targeting FAP, integrin, and VEGFR-2 foster infiltration in stroma and vasculature. TRUCK CAR-T cells secrete cytokines like IL-12 or IL-18, solHVEM, or dn TGF-ßR to overcome checkpoint inhibition. Blockage of immune checkpoint inhibition, i.e. A2aR (adenosine receptor), LAG3, TIM3, PD1, and CTLA4 can be facilitated by anti-immune checkpoint drugs or by TRUCK CARs co-expressing anti-PD1/anti-CTLA4/anti-PD-L1 antibodies. Within the TME TAMs and MDSCs secrete IDO and adenosine. Switch receptor CAR-T cells convert a dominant negative signal to positive ones, i.e. IL-4 binding ectodomain fused to IL-7 signaling endodomain or PD-1 extracellular with CD28 endodomain.

Future Directions

During the next years, we aim to identify novel T cell antigens in different cancer entities and we will develop strategies to improve CAR T cell efficiency with the goal to overcome stromal barriers and the immunosuppressive microenvironment as well as exhaustion of therapeutic T cells. Additionally, we aim to visualize the kinetics of CAR T cell function in particular their killing capacities. For that we will employ two-photon and light sheet microscopy to quantify the spatiotemporal dynamics of CAR T cell-mediated killing in appropriate mouse models or in human 3-D cell culture systems.

Selected References

  • Höpken, UE, and Rehm A. (2019). Targeting the Tumor Microenvironment of Leukemias and Lymphomas. Trends in Cancer 5, 351-364
  • Bluhm J, Kieback E, Marino, SF, Oden F, Westermann J, Chmielewski M, Abken H, Uckert W, Höpken UE*, Rehm,A* (2018). CAR T cells with enhanced sensitivity to B cell maturation antigen for the targeting of B cell non-Hodgkin’s lymphoma and multiple myeloma. Molecular Therapy 26, 1906-1919
  • Gätjen M, Brand, F, Grau, M, Gerlach, K, Kettritz, R, Westermann J, Anagnostopoulos I, Lenz, P, Lenz G, Höpken UE*, Rehm, A* (2016). Splenic marginal zone granulocytes acquire an accentuated neutrophil B cell-helper phenotype in chronic lymphocytic leukemia. Cancer Research, 76: 5253-65
  • Heinig K, Gätjen M, Grau, M, Stache, V, Anagnostopoulos I, Gerlach, K, Niesner R, Cseresnyes Z, Hauser A, Lenz P, Hehlgans T, Brink R, Westermann J, Dörken B, Lipp M, Lenz G, Rehm A, Höpken UE (2014). Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B cell activation and proliferation. Cancer Discovery 4: 1449-1465
    * equal contribution