Head: Manfred Lehner

Christian Doppler Laboratory for Next Generation CAR T Cells

We focus on the development of therapeutic strategies based on T cells modified with chimeric antigen receptors (CARs). The goal of this CD Laboratory is to generate novel molecular tools to minimize the destruction of healthy tissue and to be able to reversibly control CAR T cell activity in the patient.

Manfred Lehner
Background

T cells engineered to express Chimeric Antigen Receptors (CAR T cells) have shown impressive clinical success for patients with B cell malignancies. However, since CAR T cells are self-replicating living drugs it is difficult to regulate their function after administration to a patient, often resulting in severe side effects such as cytokine release syndrome and neurotoxicity. At the same time, currently used CAR T cells could also potentially attack healthy tissue, since their typical target antigens are always present to some extent on a small fraction of healthy cells. This lack of tumor specificity and the insufficient controllability of CAR T cell function are major hurdles for the clinical implementation of the full potential of CAR T cell therapy until today.

CD-Lab Website

For more information see: https://christian-doppler.ccri.at/

Our Research

Tackling self-replicating living drugs

Immunotherapy with CAR T cells has shown impressive clinical success for patients with B cell malignancies. However, since CAR T cells are self-replicating living drugs, it is difficult to regulate their function after administration to a patient, often resulting in severe side effects.

At the same time, currently used CAR T cells could also potentially attack healthy tissue, since their typical target antigens are always present to some extent on a small fraction of healthy cells. This lack of tumor specificity and the insufficient controllability of CAR T cell function are, to date, major hurdles for the clinical implementation of the full potential of CAR T cell therapy.

Increasing controllability of CAR T cells

In November 2019, the Christian Doppler (CD) Laboratory for Next Generation CAR T Cells was launched. In this CDL, we are working together with the University of Natural Resources and Applied Life Sciences and the industrial partner Miltenyi Biotec on solutions to increase the tumor specificity and controllability of CAR T cells – with the ultimate goal of developing new therapeutic options for high-risk childhood cancer.

For more information see: https://christian-doppler.ccri.at/

Selected Articles

Zajc CU, Salzer B, Taft JM, Reddy ST, Lehner M, Traxlmayr MW. Driving CARs with alternative navigation tools – the potential of engineered binding scaffolds. FEBS J. 2020 Aug 13. doi: 10.1111/febs.15523. PMID: 32794303 Review.

B Salzer, C M Schueller, C U Zajc, T Peters, M A Schoeber, B Kovacic, M C. Buri, E Lobner, O Dushek, J Huppa, C Obinger, E M Putz, W Holter, M W Traxlmayr, M Lehner. Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function. Nature Communications 20th August 2020. doi: 10.1038/s41467-020-17970-3

Zajc (neé Brey) CU., M. Dobersberger, I. Schaffner, G. Mlynek, D. Pühringer, B. Salzer, K. Djinović-Carugo, Steinberger P, De Sousa Linhares A, Yang NJ, C. Obinger, W. Holter, MW. Traxlmayr# & M. Lehner#. A conformation-specific ON-switch for controlling CAR T cells with an orally available drug. PNAS. 2020; doi.org/10.1073/pnas.1911154117, (# shared senior authorship)

Brey CU., J. Proff, N. Teufert, B. Salzer, J. Brozy, M. Münz, J. Pendzialek, A. Ensser, W. Holter, M. Lehner. A gB/CD3 bispecific BiTE antibody construct for targeting Human Cytomegalovirus-infected cells. Sci.Rep. 2018. 28:17453. doi: 10.1038/s41598-018-36055-2

Proff J., CU. Brey, A. Ensser, W. Holter, M. Lehner. Turning the tables on cytomegalovirus: targeting viral Fc receptors by CARs containing mutated CH2-CH3 IgG spacer domains. J.Transl.Med. 2018. 16:26. doi:

Proff J, C Walterskirchen, C Brey, R Geyeregger, F Full, A Ensser, M Lehner, W Holter. Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner. Front Microbiol. 2016, doi: 10.3389/fmicb.2016.00844.

Projects and Funding

  • CD Laboratory for “Next generation CAR-T cells”
    Head of CD Laboratory and Coordinator: Manfred Lehner
    Christian Doppler Association, Christian Doppler Lab
    Duration: 01/11/2019 to 31/10/2026

  • Regulating CAR T cells with a safe and naturally occurring drug
    CCRI responsible researcher: Elise Sylvander (supervisor: Manfred Lehner)
    Grant from the Austria Academy of Sciences (ÖAW), DOC fellowship, ID – 26323
    Duration: 01/07/2022 to 01/07/2024

Collaborating Partners

Project Partner: Michael Traxlmayr, BOKU-University of Natural Resources and Life Sciences, Vienna, Austria, Head of External Module 
Industry Project Partner: Jörg Mittelstaet, Miltenyi Biotec, Germany, Industry Partner

Team

Manfred Lehner
Head of CD-Lab
Elise Sylvander
PhD Student
Dominik Emminger
Research Assistant
Konstantina Mouratidis
Master Student