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Project 8

Optimization of HBV-specific T cells for hepatocellular carcinoma therapy

Academic Partners
Prof. Dr. med. Ulrike Protzer
Institut für Virologie der Technischen Universität München
publications
more on the person
Prof. Dr. rer. nat. Elfriede Noessner
Helmholtz Zentrum München 
publications
more on the person
Dr. Luis Felipe Olguin Contreras
Post Doc Prof. Protzer
Industry Partners
Dr. Karin Wisskirchen
SCG Cell Therapy GmbH
publications
Dr. Susanne Wilde
SCG Cell Therapy GmbH

Prof. Dr. med. Sebastian Kobold

Abt. Klinische Pharmakologie, Klinikum der Universität München

Prof. Dr. med. Georg Gasteiger

Institut für Systemimmunologie. Universität Würzburg

Project Summary



Hepatocellular carcinoma has a world-wide incidence of greater than 800.000 new cases every year. Its etiology being often associated with hepatitis B virus infection (>50% of cases) offers the unique opportunity to target viral antigens for chronic HBV treatment or specific tumor attack. However, the liver and the tumor milieu are not permissive for strong T cell function. Hence, the project aims at overcoming the immune suppression at two levels: a) by engineering the T cells to express strong antigen-specific recognition structures (T cell receptors, TCRs, or chimeric antigen receptors, CARs) and b) enhancing the T cells’ reactivity profile through antigen specific vaccination and facilitated co-stimulation using chimeric switch proteins. To bring the scientific investment to clinical benefit, the academic research is partnered with biopharma, which develops GMP conform technologies for T cell expansion and clinical application.

Debelec-Butuner B, Quitt O, Schreiber S, Momburg F, Wisskirchen K, Protzer U. Activation of distinct antiviral T-cell immunity: A comparison of bi- and trispecific T-cell engager antibodies with a chimeric antigen receptor targeting HBV envelope proteins. Frontiers in Immunology 2022, 13: 1029214e. DOI=10.3389/fimmu.2022.1029214. PMID: 36405686; PMCID: PMC9670976.

Sailer N, Fetzer I, Salvermoser M, Braun M, Brechtefeld D, Krendl C, Geiger C, Mutze K, Noessner E, Schendel DJ, Bürdek M, Wilde S, Sommermeyer D. T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity. Cancers (Basel). 2022 Apr 14;14(8):1998. doi: 10.3390/cancers14081998. PMID: 35454906; PMCID: PMC9030144.

Klopp A, Schreiber S, Kosinska AD, Pulé M, Protzer U, Wisskirchen K. Depletion of T cells via Inducible Caspase 9 Increases Safety of Adoptive T-Cell Therapy Against Chronic Hepatitis B. Front Immunol. 2021 Oct 6;12:734246. doi: 10.3389/fimmu.2021.734246. PMID: 34691041; PMCID: PMC8527178.

Olguín-Contreras LF, Mendler AN, Popowicz G, Hu B, Noessner E. Double Strike Approach for Tumor Attack: Engineering T Cells Using a CD40L:CD28 Chimeric Co-Stimulatory Switch Protein for Enhanced Tumor Targeting in Adoptive Cell Therapy. Front Immunol. 2021 Nov 29;12:750478. doi: 10.3389/fimmu.2021.750478. eCollection 2021

Quitt O, Luo S, Meyer M, Xie Z, Golsaz-Shirazi F, Loffredo-Verde E, Festag J, Bockmann JH, Zhao L, Stadler D, Chou WM, Tedjokusumo R, Wettengel JM, Ko C, Noeßner E, Bulbuc N, Shokri F, Lüttgau S, Heikenwälder M, Bohne F, Moldenhauer G, Momburg F, Protzer U. T cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice. Journal of Hepatology 2021 Nov 75(5): 1058-1071. PMID: 34171437

Schreiber, S., Honz, M., Mamozai, W., Kurktschiev, P., Schiemann, M., Witter, K., Moore, E., Zielinski, C., Sette, A., Protzer, U., Wisskirchen, K.
 Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors. Mol.Ther.-Methods Clin. Dev. 2021: 23, 476-489.

Zhao L, Chen F, Quitt O, Festag M, Ringelhan M, Wisskirchen K, Festag J, Yakovleva L, Sureau C, Bohne F, Aichler M, Bruss V, Shevtsov M, van de Klundert M, Momburg F, Möhl BS, Protzer U. Hepatitis B virus envelope proteins can serve as therapeutic targets embedded in the host cell plasma membrane. Cell Microbiol. 2021 Dec;23(12):e13399. doi: 10.1111/cmi.13399. Epub 2021 Nov 22. PMID: 34729894.

Wisskirchen K*, Kah J*, Malo A, Asen T, Volz T, Allweiss L, Wettengel JM, Lütgehetmann M, Urban S, Bauer T, Dandri M*, Protzer U*. T-Cell Receptor Grafting allows Virological Control of Hepatitis B Virus Infection. Journal Clinical Investigation 2019, 129(7):2932-2945. Doi 10.1172/JCI120228. PMID 31039136.

Festag MM, Hasreiter J, Fräßle S, Asen T, Sacherl J, Schreiber S, Mück-Häusl M, Busch D, Wisskirchen K and Protzer U. Evaluation of a fully human, hepatitis B virus-specific chimeric antigen receptor in an immunocompetent mouse model. Molecular Therapy 2019,27(5): 947-959. PMID 30852138.

Schlenker R, Olguín-Contreras LF, Leisegang M, Schnappinger J, Disovic A, Rühland S, Nelson PJ, Leonhardt H, Harz H, Wilde S, Schendel DJ, Uckert W, Willimsky G, Noessner E. 2017. Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy. Cancer Res. 77(13):3577-3590. doi: 10.1158/0008-5472.CAN-16-1922. Epub 2017 May 22.

Wisskirchen K, Metzger K, Schreiber S, Asen T, Weigand L, Dargel C, Witter K, Kieback E, Sprinzl MF, Uckert W, Schiemann M, Busch DH, Krackhardt AM, Protzer U.

Isolation and functional characterization of hepatitis B virus-specific T-cell receptors as new tools for experimental and clinical use. PLoS One. 2017 Aug 8;12(8): e0182936. PMID: 28792537