Christian Doppler Laboratory

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

Dobersberger M, Sumesgutner D, Zajc CU, Salzer B, Laurent E, Emminger D, Sylvander E, Lehner E, Teufl M, Seigner J, Bobbili MR, Kunert R, Lehner M, Traxlmayr MW (2024). An engineering strategy to target activated EGFR with CAR T cells. Cell Rep Methods 22;4(4):100728. doi: 10.1016/j.crmeth.2024.100728.

Heitzeneder S, Bosse KR, Zhu Z, Zhelev D, Majzner RG, Radosevich MT, Dhingra S, Sotillo E, Buongervino S, Pascual-Pasto G, Garrigan E, Xu P, Huang J, Salzer B, Delaidelli A, Raman S, Cui H, Martinez B, Bornheimer SJ, Sahaf B, Alag A, Fetahu IS, Hasselblatt M, Parker KR, Anbunathan H, Hwang J, Huang M, Sakamoto K, Lacayo NJ, Klysz DD, Theruvath J, Vilches-Moure JG, Satpathy AT, Chang HY, Lehner M, Taschner-Mandl S, Julien JP, Sorensen PH, Dimitrov DS, Maris JM, Mackall CL (2022). GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. Cancer Cell 40, 53-69.e59

Salzer B, Schueller CM, Zajc CU, Peters T, Schoeber MA, Kovacic B, Buri MC, Lobner E, Dushek O, Huppa JB, Obinger C, Putz EM, Holter W, Traxlmayr MW, Lehner M (2020). Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function. Nat Commun 11, 4166.

Zajc CU, Dobersberger M, Schaffner I, Mlynek G, Pühringer D, Salzer B, Djinović-Carugo K, Steinberger P, De Sousa Linhares A, Yang NJ, Obinger C, Holter W, Traxlmayr MW*, Lehner M* (2020). A conformation-specific ON-switch for controlling CAR T cells with an orally available drug. Proc Natl Acad Sci U S A 117, 14926-14935. (*, shared senior and corresponding authorship)

Pascoal S*, Salzer B*, Scheuringer E, Wenninger-Weinzierl A, Sturtzel C, Holter W, Taschner-Mandl S, Lehner M, Distel M (2020). A Preclinical Embryonic Zebrafish Xenograft Model to Investigate CAR T Cells In Vivo. Cancers (Basel) 12. (*, shared first authorship)

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

Improving tumor specificity of cellular immunotherapies CCRI responsible researcher: Manfred Lehner Grant from the Austrian Science Fund (FWF), Stand-Alone Project, ID – PAT8789924 01/11/2024 – 31/10/2028

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