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.
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.
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.
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
Grissenberger S, Salzer B, Pascoal S, Wenninger-Weinzierl A, Lehner M*, Distel M* (2022). Preclinical testing of CAR T cells in zebrafish xenografts. Methods Cell Biol, 167, 133-147. (*, shared corresponding authorship)
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)
Brey CU, Proff J, Teufert N, Salzer B, Brozy J, Münz M, Pendzialek J, Ensser A, Holter W, Lehner M (2018). A gB/CD3 bispecific BiTE antibody construct for targeting Human Cytomegalovirus-infected cells. Sci Rep, 8, 17453.
Proff J, Brey CU, Ensser A, Holter W, Lehner M (2018). Turning the tables on cytomegalovirus: targeting viral Fc receptors by CARs containing mutated CH2-CH3 IgG spacer domains. J Transl Med, 16, 26.
Zajc CU, Salzer B, Taft JM, Reddy ST, Lehner M*, Traxlmayr MW* (2021). Driving CARs with alternative navigation tools – the potential of engineered binding scaffolds. Febs J, 288, 2103-2118. (*, shared senior and corresponding authorship)
Worel N, Grabmeier-Pfistershammer K, Kratzer B, Schlager M, Tanzmann A, Rottal A, Körmöczi U, Porpaczy E, Staber PB, Skrabs C, Herkner H, Gudipati V, Huppa JB, Salzer B, Lehner M, Saxenhuber N, Friedberg E, Wohlfarth P, Hopfinger G, Rabitsch W, Simonitsch-Klupp I, Jäger U, Pickl WF (2022). The frequency of differentiated CD3(+)CD27(-)CD28(-) T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. Front Immunol, 13, 1004703.
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
