At the LIT, research in our Division focuses on two main areas. Firstly, we look at the molecular and cellular mechanisms of CAR-redirected T-cell activation to develop multifunctional CARs for redirected antitumor activities. Secondly, we seek to translate newly developed, first-in-class CARs into clinical trials for the treatment of hematologic and solid cancers.

The focus of our research

The team’s goal is to try and understand how a signaling CAR synapse is formed on the spatial/temporal level, and which components of the T-cell membrane—particularly of the TCR—are actively involved. Protein-structure modeling will enable us to improve the CAR structure itself by modifying the synapse in favor of more durable T-cell activation. Bioinformatic tools developed by our own group enable us to identify and track productive CAR T-cell interactions in time and space at a microscopic level.

The driving forces limiting CAR T-cell efficacy are thought to be accelerated exhaustion—caused by intrinsic mechanisms—and repression—caused by extrinsic signals. With this identified, we seek to find ways to counteract these mechanisms in order to prolong T-cell activation and ultimately the antitumor response. We are currently approaching this in three ways:

Firstly, we add a cytokine signal (‘signal-3’) to the CAR T cell by transgenic expression of cytokines. CAR T cells delivering a transgenic protein (TRUCKs) or harboring the cytokine integrated in the CAR or the T cell membrane (CHICs; Cytokine help intensified CAR T cells) are engineered to modulate the tumor stroma or the T cell itself to create a more favorable environment for an inflammatory immune response.
Secondly, we interfere with downstream signaling molecules to prolong CAR T-cell activation.
Thirdly, we are counteracting CAR T-cell repression from the tumor stroma by adding a positive stimulatory signal that overruns repressive signals coming from the tumor environment.

Moving research forward:

The team recently developed the concept of a IL18-releasing TRUCK that conveys a superior antitumor response. We are currently involved in translating this concept into a multi-center phase-I trial, targeting GD2+ tumors in both pediatric and adult patients. The trial is being funded by the Federal Ministry of Education and Research (BMBF). And the consortium involved is coordinated by Professor Claudia Rössig from the University of Münster.

We shine the spotlight on this special research project. For more information click here to visit the page “Featured Project – CAR T cells engineered to act as ‘living factories’”!

Continued divisional research

The Division has developed a novel CAR format by adding IL12 to the CAR’s extracellular moiety that enables engineered T cells to eliminate antigen-loss cancer cells in an NK-like fashion. Together with Professor Simone Thomas, we are looking to develop this further by redirecting CD19 CAR T cells with integrated IL12 towards leukemia/lymphoma cells that experience CD19 antigen loss. Such IL12-CD19 CAR T cells are thought to reduce leukemia/lymphoma relapse after primary tumor reduction.
Novel first-in-class CAR constructs were recently developed by our Division to trigger a more efficacious T-cell antitumor response. Specifically, we engineered an antitumor CAR that also blocks the CD30-CD30L interaction on the engineered T cell itself, thereby prolonging a redirected antitumor response. Again—in close cooperation with Professor Thomas—we are now in the preparatory phase for a multi-center trial for the treatment of metastatic CEA+ gastrointestinal cancer using CEA-CD30 CAR T cells that exhibit prolonged and improved T-cell activation on CD30 blockade in CAR T cells. We also want to elucidate the underlying mechanism of action. Moreover, we are looking to engineer more efficacious CAR formats using bioinformatic protein-modeling in cooperation with Professor Jens Meiler, University of Leipzig.
In another research field, the Division is developing strategies to redirect regulatory T cells (Tregs) towards tissues affected by autoimmune diseases. To this end, we are engineering CARs to activate and amplify Tregs to reduce inflammatory reactions at a specific localized site.

Visit the complete list of our Research Division’s publications on PubMed:

https://pubmed.ncbi.nlm.nih.gov/?term=abken-h&sort=date

Here is a selection of the most important publications from the last few years:

Barden, M., Holzinger, A., Velas, L., Mezősi-Csaplár, M., Szöőr, A., Vereb, G., Schütz, G. J., Hombach, A. A., Abken, H., CAR and TCR form individual signaling synapses and do not cross-activate, however, can co-operate in T cell activation. Frontiers Immunol., 14: 1110482 (2023) doi: 10.3389/fimmu.2023.1110482

Hombach, A.A., Barden, M., Hannappel, L., Chmielewski, M., Rappl, G., Sachinidis, A., Abken, H., IL12 integrated into the CAR exodomain converts CD8+ T cells to poly-functional NK-like cells with superior killing of antigen-loss tumors. Mol. Ther. 30, 593 – 605 (2022). doi: 10.1016/j.ymthe.2021.10.011

Blokon-Kogan, D., Levi-Mann, M., Malka-Levy, L., Itzhaki, O., Besser, M.J., Shiftan, Y., Szöőr, A., Vereb, G., Gross, G., Abken, H., Weinstein-Marom, H., Membrane anchored IL-18 linked to constitutively active TLR4 and CD40 improves human T cell anti-tumor capacities for adoptive cell therapy. J. Immunother. Cancer, 10, e001544 (2022), doi: 10.1136/jitc-2020-001544

Bunse, M., Pfeilschifter, J., Bluhm, J., Zschummel, N., Foedicke, J. J., Wirges, A., Stark, H., Kretschmer, V., Chmielewski, M., Uckert, W., Abken, H., Westermann, J., Rehm, A., Höpken, U. E., CXCR5 CAR-T cells simultaneously target B cell Non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells. Nat. Comm. 12, 240 (2021). doi: 10.1038/s41467-020-20488-3

Abken, H., Building on synthetic immunology and T cell engineering: a brief journey through the history of chimeric antigen recep. Hum. Gene Ther., 32, 1011-1028 (2021). doi.org/10.1089/hum.2021.165

Overbeck, S., Schrader, A., Warner, K., Jungherz, D., Crispatzu, G., von Jan, J., Chmielewski, M., Ianevski, A., Diebner, H. H., Mayer, P., Ados, A. K., Wahschaffe, L., Braun, T., Müller, T., Wagle, P., Bouska, A., Neumann, T., Pützer, S., Varghese, L., Pflug, N., Thelen, M., Makalowsli, J., Riet, N., Göx, H., Rappl, G., Altmüller, J., Kotrova, M., Persigehl, T., Hopfinger, G., Hansmann, M.L., Schloesser, H., Stilgenbauer, S., Dürig, J., Mougiakakos, D., von Bergwelt-Baildon, M., Roeder, I., Hartmann, S, Hallek, M., Moriggl, R., Brüggemann, M., Aittokallio, T., Iqbal, J., Newrzela, S., Abken, H., Herling, M., Non-canonical effector functions of the T-memory-like T-PLL are shaped by cooperative TCL1A and TCR signaling. Blood 136, 2786 – 2802 (2020), doi: 10.1182/blood.2019003348

Dragon, A. C., Zimmermann, K., Nerreter, T., Sandfort, D., Lahrberg, J., Klöß, S., Kloth, C., Mangare, C., Bonifacius, A., Tischer-Zimmermann, S., Blasczyk, R., Maecker-Kolhoff, B., Uchanska-Ziegler, B., Abken, H., Schambach, A., Hudecek, M, Eiz-Vesper, B., CAR-T cells and TRUCKs that recognize an EBNA-3C-derived epitope presented on HLA-B*35 control Epstein-Barr virus-associated lymphoproliferation. J. ImmunoTher Cancer 8: e000736 (2020), doi: 10.1136/jitc-2020-000736.

Hombach, A.A., Rappl, G., Abken, H., Blocking CD30 on T cells by a dual specific CAR for CD30 and colon cancer antigens improves the CAR T cell response against CD30 negative tumors. Mol. Ther. 27, 1825 – 1835 (2019), doi: 10.1016/j.ymthe.2019.06.007.

Golumba-Nagy, V., Kuehle, J., Hombach, A.A., Abken, H., CD28-ζ CAR T Cells Resist TGF-β Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop. Mol. Ther. 26, 2218 – 2230 (2018), doi: 10.1016/j.ymthe.2018.07.005

Bluhm, J., Kieback, E., Marino, S.F., Oden, F., Westermann, J., Chmielewski, M., Abken, H., Uckert, W., Höpken, U.E., Rehm, A., CAR T cells with enhanced sensitivity to B cell maturation antigen for the targeting of cell non-Hodgkin’s lymphoma and multiple myeloma. Mol. Ther. 26, 1906 – 1920 (2018), doi: 10.1016/j.ymthe.2018.06.012

Our research work into CAR T cells aims to harness these novel basic developments in the production of effective immunotherapies for patients. Together with Professor Simone Thomas, we are currently establishing a clinical phase-I trial that explores a next-generation CAR design for the treatment of patients with metastatic colorectal cancer. In cooperation with Professor Rössig, Münster, and Professor Mackensen, Erlangen, we are conducting a phase I trial for the therapy of GD2+ pediatric and adult tumors.

Many thanks to the funding agencies who support our work:

Wilhelm Sander Stiftung
‘Verbesserung der CAR T-Zell Wirksamkeit gegen Leukämie/Lymphome mit Antigen-verlust durch ein neues CAR-Design, das CAR-T-Zellen mit NK-ähnlichen Fähigkeiten ausstattet.’

Website WSSt

German Cancer Aid – Deutsche Krebshilfe
‘A phase-I safety, dose finding and feasibility trial of RCI-CART-CEA/30 in patients with CEA positive liver metastases from colorectal cancer.’

Website DKH

Federal Ministry for Education and Research (BMBF)
‘Klinische Phase I-Studie der Sicherheit, Dosisfindung und Machbarkeit einer adoptiven T-Zell-Therapie mit GD2-IL18 CART bei Patient(inn)en mit rezidivierten oder refraktären GD2-positiven soliden Tumoren’ (GD2-IL18 TRUCK Konsortium)

Website BMBF

Federal Ministry for Education and Research (BMBF)
‘Confirmatory studies on the value of C-C-motive receptor-8’ (CONTRACT Konsortium)

Website BMBF

Novo Nordisk Fonden
‘Nanomaterials for efficacious cancer immunotherapy’ (NICE Konsortium)

Website NNF

European Innovation Council (EIC)
Pathfinder Open Grant, ‘CAR T cells rewired to prevent exhaustion in the tumor microenvironment’ (CAR T-REX Konsortium)

Website EIC

Prof. Hinrich Abken

Head of Research Division | Genetic Immunotherapy

Tel: +49 941 944–38111
Email: hinrich.abken@ukr.de

Research team

Prof. Hinrich Abken

Head of Research Division | Genetic Immunotherapy

Markus Barden

Postdoctoral Scientist

Dr. Astrid Holzinger

Postdoctoral Scientist

Dr. Hong Pan

Postdoctoral Scientist

Dr. Dennis Harrer

Postdoctoral Scientist

Valerie Bezler

PhD Student

Celine Dreger

PhD Student

Patrick Elsenbroich

MD Student

Anja Pavlica

Research Technician

Lab Life

There is life outside the laboratory: The Leibniz Institute places great value on our scientists developing the team spirit both in and out of work. Here are the photos to prove it!