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2. Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies

Author

Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C.D., Nieper, P., Feldmann, T., Merkel, O., Lorsy, E., da Palma Guerreiro, A., von Jan, J., Kisis, I., Wasserburger, E., Claasen, J., Faitschuk-Meyer, E., Altmüller, J., Nürnberg, P., Yang, T.-P., Lienhard, M., Herwig, R., Kreuzer, K.-A., Pallasch, C.P., Büttner, R., Schäfer, S.C., Hartley, J., Abken, H., Peifer, M., Kashkar, H., Knittel, G., Eichhorst, B., Ullrich, R.T., Herling, M., Reinhardt, H.C., Hallek, M., Schweiger, M.R., and Frenzel, L.P.

Published
2022
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4. Noncanonical effector functions of the T-memory–like T-PLL cell are shaped by cooperative TCL1A and TCR signaling

Author

Oberbeck, S., Schrader, A., Warner, K., Jungherz, D., Crispatzu, G., von Jan, J., Chmielewski, M., Ianevski, A., Diebner, H.H., Mayer, P., Kondo Ados, A., Wahnschaffe, L., Braun, T., Müller, T.A., Wagle, P., Bouska, A., Neumann, T., Pützer, S., Varghese, L., Pflug, N., Thelen, M., Makalowski, J., Riet, N., Göx, H.J.M., Rappl, G., Altmüller, J., Kotrová, M., Persigehl, T., Hopfinger, G., Hansmann, M.L., Schlößer, 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., and Herling, M.

Published
2020
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14. A recombinant anti-carcinoembryonic antigen immunoreceptor with combined CD3(zeta)-CD28 signalling targets T cells from colorectal cancer patients against their tumour cells

Author

Hombach, A., Schlimper, C., Sievers, E., Frank, S., Schild, H.H., Sauerbruch, T., Schmidt-Wolf, I.G.H., and Abken, H.

Subjects
Colorectal cancer -- Research, Colorectal cancer -- Physiological aspects, Colorectal cancer -- Diagnosis, Cancer patients -- Research, Cancer patients -- Physiological aspects, T cells -- Research, T cells -- Physiological aspects, Health
Published
2006

16. An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn's disease and experimental colitis in vivo

Author

Stallmach, A., Marth, T., Weiss, B., Wittig, B.M., Hombach, A., Schmidt, C., Neurath, M., Zeitz, M., Zeuzem, S., and Abken, H.

Subjects
Health
Abstract

Gut 2004;53:339-345. doi: 10.1136/gut.2003.020107 Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn's disease (CD). Since IL-12 p40 dimers act as [...]

Published
2004

30. Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies

Author

Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C.D., Nieper, P., Feldmann, T., Merkel, O., Lorsy, E., da Palma Guerreiro, A., von Jan, J., Kisis, I., Wasserburger, E., Claasen, J., Faitschuk-Meyer, E., Altmüller, J., Nürnberg, P., Yang, T.-P., Lienhard, M., Herwig, R., Kreuzer, K.-A., Pallasch, C.P., Büttner, R., Schäfer, S.C., Hartley, J., Abken, H., Peifer, M., Kashkar, H., Knittel, G., Eichhorst, B., Ullrich, R.T., Herling, M., Reinhardt, H.C., Hallek, M., Schweiger, M.R., and Frenzel, L.P.

Abstract

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Since there is no common genetic alteration causing resistance to venetoclax in CLL and B cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole exome sequencing, methylated DNA immunoprecipitation sequencing and genome wide CRISPR/Cas9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMApromoter which is methylated upon venetoclax treatment, mediating PUMAdownregulation on transcript and protein level. PUMAexpression and sensitivity towards venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher OXPHOS and ATP production, resembling the metabolic phenotype that is seen upon venetoclax resistance. While PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity towards both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter’s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive DLBCL in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Published
2024
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34. Absract

Author

Kaszkin, Marietta, Kinzel, Volker, Maly, Karl, Bichler, Irina, Lang, Florian, Grunicke, Hans H., Pepperkok, R., Jakobi, R., Lorenz, P., Ansorge, W., Pyerin, W., Borowski, P., Harbers, M., Ludwig, A., Kischel, T., Hilz, H., Eckert, K., Granetzny, A., Fischer, J., Grosse, R., Manch, V., Wehner, S., Kornhuber, B., Ebener, U., Müller-Decker, K., Fürstenberger, G., Vogt, I., Marks, F., Graschew, G., Küsel, A., Hull, W., Lorenz, W., Thielmann, H. W., Degen, Gisela H., Freyberger, Alexius, Müller, A., Linscheid, M., Hindermeier, Ulrike, Jorritsma, Ute, Golka, K., Föllmann, W., Peter, H., Bolt, H. M., Monnerjahn, S., Phillips, D. N., Never, A., Seidel, A., Glatt, A. R., Wiench, K., Frei, E., Schroth, P., Wiessler, M., Schäfer, T., Hergenhahn, M., Hecker, E., Proft, D., Bartholmes, P., Bagewadikar, R. S., Bertram, B., Frank, N., Leibersperger, Hanno, Gschwendt, Michael, Marks, Friedrich, Fasco, S., Plein, Peter, Schiess, Karin, Seidler, Lothar, Jacobi, T., Besemfelder, E., Stephan, M., Lehmann, W. D., Grell, M., Thoma, B., Scheurich, P., Meyer, Markus, Grunicke, Hans, Jaques G., Wegmann B., Ravemann K., Popanda, Odilia, Thielmann, Heinz Walter, Voss, H., Wirkner, U., Werner, Dieter, Strand, D., Kalmes, A., Walther, H. -P., Mechler, B., Schirrmacher, S. Volker, Kinzel, V., Hess, R., Hanagarth, H. -G., Hässler, C., Brandner, G., Ertel, Christian, Gückel, B., Schirrmacher, V., Kyewski, B. A., Bogdahn U., Jachimczak P., Schneider J., Brysch W., Schlingensiepen W., Drenkard D., Behl C., Winkler J., Apfel R., Meixensberger J., Stulle, K., Marquardt, P., Vollmers, H. P., Müller, J., Müller-Hermelink, H. -K., Schuermann, M., Seemann, G., Ptok, Angelika, Ptok, M., Carey, T. E., Steffen M., Nitz U. C., Everding B., Hölzel F., Kantwerk-Funke, G., Boll, G., Zänker, K. S., Everding, B., Steffen, M., Hölzel, P., Heymanns, J., Hennig, C., Rotsch, M., Havemann, K., Fischer, Jürgen R., Stehr, Sabine, Lahm, Harald, Drings, Peter, Krammer, Peter H., Kirsch M., Strubel A., Kist A., Hinn R., Fischer H., Buttler A., Schackert G., Friedenauer, S., Lindner, D., Marczynski, B., Karcls, H., Goergens, H. W., Epe, B., Müller, E., Schütze, D., Boiteux, S., Eder, E., Deininger, C., Hoffman, C., Scherer, E., Vermeulen, E., van Kranen, H. J., Bax, J., Woutersen, R. A., van Kreijl, C. F., Schurich, B., Hagedorn, H., Kamp, E., Eisenbrand, G., Spiegelhalder B., Bolm-Audorff U., Bienfait H. G., Preussmann R., Wacker, C. -D., Preussmann, R., Kehl, H., Spiegelhalder, B., Akkan, Z., Ries, J., Meger, M., Shephard, S. E., Gunz, D., Lutz, W. K., Tricker, A. R., Kurnar, R., Siddiqi, M., Mende, P., Pfundstein, B., Scholl, A., Janzowski, C., Jacob, D., Goelzer, P., Henn, I., Zankl, H., Zimlich, K. -H., Gansewendt, Barbara, Thier, Ricarda, Schroeder, K. R., Hallier, E., Moeckel, G., Heiden, W., Waldherr-Teschner, M., Brickmann, J., Roeser, H., Krauter, G., Scherer, G., Krätschmer, A., Hauenstein, H., Adlkofer, F., Fernando, R. C., Schmeiser, H. H., Nicklas, W., Pfau, Wolfgang, Phillips, David H., Scheckenbach, S., Cantoreggi, S., Leutbecher, Monika, Ottenwälder, H., Föst, U., Baumgart, P. M., Kliem, H. -C., Data, S., Pfeiffer, C., Fuchs, A., Schmezer, P., Kuchenmeister, F., Pool-Zober, B. L., Liegibel, U. M., Pool-Zobel, B. L., Steeb, L., Friesel, H., Schneider, Th., Scherf, H. R., Buchmann, A., Bauer-Hofmann, R., Mahr, J., Schwarz, M., Schmidt, R., Rippmann, F., Steinbauer, B., Zlfu, P., Bunk, B., Hefter, W., Klinga, K., Berger, M. R., Robertson, L. W., Luebeck, G., Moolgavkar, S., Torsten U., Kowalczyk-Wagner M., Weitzel H., Zechel, Ch., Peters, H., Anders, F., Ambs, S., Kirchner, T., Neumann, H. -G., Einig, C., Eigenbrodt, E., Oesterle, D., Deml, E., Weisse, G., Gerbracht, U., Stumpf, H., Filsingcr, E., Bannasch, P., Muster, W., Cikryt, P., Münzel, P., Röhrdanz, E., Bock, K. W., Lipp, H. -P., Wiesmüller, T., Hagenmaier, H., Schrenk, D., Karger, A., Bauer, G., Höfler, P., Götschl, M., Viesel, E., Jürgensmeier, J., Schaefer, D., Picht, G., Kiefer, J., Krieg, P., Schnapke, R., Feil, S., Wagner, E., Schleenbecker, U., Anders, A., Gross, M. M., Unger, S., Stanbridge, E. J., Boukamp, Petra, Pascheberg, Ulrich, Fusenig, Norbert E., Abken, H., Weidle, U. H., Grummt, F., Willecke, K., Schäfer, R., Hajnal, A., Balmer, I., Klemenz, R., Goretzki, P. E., Reishaus, H., Demeure, M., Haubruck, H., Lyons, J., Röher, H. D., Trouliaris, Sylvia, Hadwiger-Fangmeier, Angelika, Simon, Elke, Niemann, Heiner, Tamura, Teruko, Westphal, G., Turner, Elke, Karels, H., Blaszkewicz, M., Stopper, Helga, Schiffmann, Dietmar, De Boni, Umberto, Schuler, M., Schnitzler, R., Metzler, M., Pfeiffer, E., Aulenbacher, R., Langhof, T., Schröder, K. R., Saal, K., Müller-Hermelink, H. K., Henn W., Seitz G., Lagoda P., Christmann A., Blin N., Welter C., Adam, D., Fömzler, D., Winkler, C., Mäueler, W., Schartl, M., Theisinger B., Schüder G., Rüther U., Nunnensiek C., Müller H. A. G., Rupp W., Lüthgens M., Jipp P., Kinzler, I., Gulich, M., Seidel, H. J., Clark, O. H., McCormick, F., Bourne, H. R., Gieseler, F., Boege, F., Biersack, H., Spohn, B., Clark, M., Wilms, K., Boege, Fritz, Gieseler, Frank, Biersack, Harald, Clark, Michael, Wllms, Klaus, Polack, Axel, Strobl, Lothar, Feederle, Regina, Schweizer, Matthias, Eick, Dirk, Bornkamm, Georg W., Kopun M., Scherthan H., Granzow C., Janiaud, P., Rueß, D., Mechler, B. M., Strauss, P. G., Erfle, V., Fritsche, M., Haessler, C., Christiansen, H., Schestag, J., Christiansen, N. M., Lampert, F., Schulz, Wolfgang A., Hasse, Andreas, Sies, Helmut, Orend, G., Kuhlmann, I., Doerfler, W., Behn-Krappa, A., Hölker, I., Sandaradura de Silva, U., Smola, Ute, Hennig, Dagmar, Hadviger-Fangmeier, Angelika, Schütz, Burkhard, Kerler R., Rabes H. M., Dölken, G., Fauser, A. A., Kerkert, R., Ragoczy, U., Fritzen, R., Lange, W., Finke, J., Nowicki, B., Schalipp, E., Siegert, W., Mertelsmann, R., Schilling, U., Sinn, H. J., Maier-Borst, W., Friedrich, E. A., Löhde E., Lück M., Raude H., Schlicker H., Barzen G., Kraas E., Milleck, J., Keymer, R., Störkel, S., Reichert, T., Steinbach, F., Lippold, R., Thoenes, W., Wagner, W., Reiffen, K. -A., Bardosi, A., Brkovic, D., Gabius, H. -J., Brandt B., Jackisch C., Seitzer D., Hillebrand M., Habermann, F. A., Rabes, H. M., Zeindl-Eberhart, Evelyn, Robl, C., Röttgen, V., Nowak, C., Richter-Reichhelm, H. -B., Waldmann, V., Suchy, B., Zietz, Ch., Sarafoff, M., Ostermayr, Richard, Rabes, Hartmut M., Lorenz, J., Friedberg, T., Paulus, W., Ferlinz, R., Oesch, F., Jähde, E., Glüsenkamp, K. -H., Tietze, L. F., Rajewsky, M. F., Chen, G., Hutter, K. -J., Bullerdiek, J., Zeller, W. J., Schirner, M., Schneider, M. R., Zbu, P., Gebelein, M., Naser-Hijazi, B., Hynes, Nancy E., Reinhardt, M., Heyl, P., Schmähl, D., Presek, P., Liebenhoff, U., Findik, D., Hartmann, G. H., Fischer, H., Kliesch, C., Schackert, G., Albert, F., Kunze, S., Wannnenmacher, M., Boese-Landgraf, J., Lorenz, E., Albrecht, D., Dulce, M., Aigner, K. R., Thiem, N., Müller, H., Leonardi, M., Bogdahn, U., Justh, A., Drenkard, D., Lutz, M., Apfel, R., Behl, C., Lang, E., Lieth, C. W. v. d., Sinn, H., Betsch, B. R., Hengstler, Jan Georg, Fuchs, Jürgen, Oesch, Franz, Busch, F. J., Cato, A. B. C., Schied, G., Tang, W., Bogdahn U., Richter B., Schaefer, C., Kelleher, D. K., Vaupel, P., Mundt, D., Bartsch, H. H., Meden, H., Meyer, M., Vehmeyer, K., Mull, R., Kuhn, W., Hoffmann, S., Berger, D., Fiebig, H., Moog, Ch., Luu, B., Frühauf, S., Keppler, B. K., Galeano, A., Valenzuela-Paz, P., Klenner, T., Stadler, H., Golomb, G., Breuer, E., Voegeli, R., Hilgard, P., Nowrousian, H. R., Aulenbacher, P., Winterhalter, B., Granson, C., Stöhr, M., Ponstingl, H., Granzow, C., Drings, P., Osswald, H., Sobottka, S. B., Amtmann, E., Sauer, G., Hornung, B., Volland, S., Kahl, S., Gerspach, R., Matz, B., Schmidt, J., Lipp, M., Brehm, G., Luz, A., Rüther, U., Wendel, S., Strauß, P. G., Erflte, V., Greehmann, S., Zobel, A., Kalkbrenner, F., Vorbrüggen, G., Moelling, K., Iftner, T., Müller, A. H., Fuchs, P. G., Pfister, H., Cichutek, Klaus, Treinies, Iris, Lang, Matthias, Braun, C., Denner J., Norley S., Kurth R., Music, L., Wiestler, O. D., Aguzzi, A., von Deimling, A., Schneemann, M., Elbl, R., Kleihues, P., Land, H., Hohn, H. -P., Höök, M., Denker, H. -W., Kemmner, W., Zaar, K., Jones, Peter A., Kath, R., Herlyn, M., Maier, P., Schawalder, H. P., Elsner, J., Parzefall, W., Erber, E., Sedivy, R., Schulte-Hermann, R., Hemmer, J., Tomakidi, P., Boukamp, P., Breitkreutz, D., Fusenig, N. E., Kallinowski, F., Strauss, W., Brownell, A. L., Bassukas, I. D., Vester, G., Maurer-Schultze, B., Langbein, L., Kosmehl, H., Katenkamp, D., Spiess, Eberhard, Trefz, Günther, Ebert, Werner, Jordan, Peter, Kübler, Dieter, Lichtner, Rosemarie B., Wiedemuth, Marion, Kittmann, Annette, Ullrich, Axel, Khazaie, Khashayarsha, Kowitz, Aiga, Kadmon, Guni, Altevogt, Peter, Frixen, U. H., Behrens, J., Schipper, J., Sachs, M., Birchmeier, H., Hackenberg, R., Hawighorst, Th., Hofmann, J., Beato, H., Schulz, K. -D., Erbil, C., Maasberg, M., Kunz, L. A., Simm, A., Adam, G., Mueller-Klieser, W., Kaufmann, Andreas M., Stoeck, Michael, Hülsen A., Boukamp P., Game S., Donnelly M., Fusenig N. E., Stark, H. -J., Schlingensiepen K. -H., Kurzik-Dumke U., Phannavong B., Gundacker D., Gateff E., Gabius, S., Joshi, S. S., Franz, H., John, N. J., Grümmer, R., Denker, H. W., Gross, M. W., and Karbach, U.

Published
1991
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35. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelop proteins control virus replication in mice

Author

Krebs, K., Böttinger, N., Huang, L.R., Chmielewski, M., Arzberger, S., Gasteiger, G., Jäger, C., Schmitt, E., Bohne, F., Aichler, M., Uckert, W., Abken, H., Heikenwalder, M., Knolle, P., and Protzer, U.

Subjects
Cancer Research, virus diseases
Abstract

BACKGROUND & AIMS: Antiviral agents suppress hepatitis B virus (HBV) replication but do not clear the infection. A strong effector T-cell response is required to eradicate HBV, but this does not occur in patients with chronic infection. T cells might be directed toward virus-infected cells by expressing HBV-specific receptors, and thereby clear HBV and help to prevent development of liver cancer. In mice, we studied whether redirected T cells can engraft following adoptive transfer, without prior T-cell depletion, and whether the large amounts of circulating viral antigens inactivate the transferred T cells or lead to uncontrolled, immune-mediated damage. METHODS: CD8(+) T cells were isolated from mice and stimulated using an optimized protocol. Chimeric antigen receptors (CARs) that bind HBV envelope proteins (S-CAR) and activate T cells were expressed on the surface of cells using retroviral vectors. S-CAR-expressing CD8(+) T cells, which carried the marker CD45.1, were injected into CD45.2(+) HBV transgenic mice. We compared these mice with mice that received CD8(+) T cells induced by vaccination, cells that express a CAR without a proper signaling domain, or cells that express a CAR that does not bind HBV proteins (controls). RESULTS: CD8(+) T cells that expressed HBV-specific CARs recognized different HBV subtypes and were able to engraft and expand in immune-competent HBV transgenic mice. Following adoptive transfer, the S-CAR-expressing T cells localized to and functioned in the liver; they rapidly and efficiently controlled HBV replication, compared with controls, causing only transient liver damage. The large amount of circulating viral antigen did not impair or over-activate the S-CAR grafted T cells. CONCLUSION: T cells with a CAR specific for HBV envelop proteins localize to the livers of mice to reduce HBV replication, causing only transient liver damage. This immune-cell therapy might be developed for patients with chronic hepatitis B, regardless of their HLA-type.

Published
2013

36. Chimeric antigen receptors for T-cell based therapy

Author

Cheadle, EJ, Sheard, V, Hombach, A, Chmielelewski, M, Riet, T, Catsman - Berrevoets, Coriene, Schooten, Erik, Lamers, Cor, Abken, H, Debets, Reno, Gilham, DE, Chames, P, Neurology, and Medical Oncology

Published
2012

37. Can Engineered 'Designer' T Cells Outsmart Chronic Hepatitis B?

Author

Protzer, U. and Abken, H.

Subjects
Article Subject
Abstract

More than 350 million people worldwide are persistently infected with human heptatitis B virus (HBV) and at risk to develop liver cirrhosis and hepatocellular carcinoma making long-term treatment necessary. While a vaccine is available and new antiviral drugs are being developed, elimination of persistently infected cells is still a major issue. Recent efforts in adoptive cell therapy are experimentally exploring immunotherapeutic elimination of HBV-infected cells by means of a biological attack with genetically engineered “designer” T cells.

Published
2010
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38. Development of adoptive cell therapy for cancer: a clinical perspective

Author

Hawkins, R. E., Gilham, D. E., Debets, R., Eshhar, Z., Taylor, N., Abken, H., Schumacher, T. N., Consortium, Attack, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Medical Oncology

Subjects
Adoptive cell transfer, T-Cell/genetics/immunology T-Lymphocytes/immunology Tissue Therapy Translational Medical Research, Genetic enhancement, T-Lymphocytes, Nervous System Neoplasms, Cell- and Tissue-Based Therapy, Receptors, Antigen, T-Cell, Translational research, Bioinformatics, Cancer Vaccines, Cell therapy, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, Immune system, Lymphocytes, Tumor-Infiltrating, Antigen, SDG 3 - Good Health and Well-being, Neoplasms, Genetics, Medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Adoptive Transfer Cancer Vaccines Clinical Trials as Topic Genetic Engineering Humans Lymphocytes, Clinical Trials as Topic, business.industry, Cancer, medicine.disease, Adoptive Transfer, Tumor-Infiltrating/immunology Neoplasms/immunology/*therapy Nervous System Neoplasms Receptors, 3. Good health, Clinical trial, 030220 oncology & carcinogenesis, Immunology, Molecular Medicine, business, Genetic Engineering, 030215 immunology
Abstract

Adoptive cellular therapy provides the promise of a potentially powerful general treatment for cancer. Although this is a complex and challenging field, there have been major advances in basic and translational research resulting in clinical trial activity that is now beginning to confirm this promise. However, these trials are also identifying new challenges and this review focuses on these clinical issues. For tumors such as melanoma, in which tumor-specific T cells can be readily identified and isolated, the adoptive transfer of "tumor-infiltrating lymphocytes'' (TILs) already appears to offer significant patient benefit and this approach now warrants further development. Genetically engineered T cells offer a means to endow peripheral blood T cells with antitumor activity and in principle these techniques could allow the treatment of a wide range of cancers. Genetic engineering also offers the means to endow T cells with new properties and enhanced functions. There have been clear proof-of-principle trials showing responses with T cell receptor (TCR)-engineered T cells and this can be built on with further development. By contrast, other trials have produced significant toxicity related to expression of target antigen on normal tissue, particularly with enhanced receptors. The challenge ahead lies in understanding how to achieve the balance between targeted antitumor immune responses while avoiding toxicity associated with on-target destruction of antigen-expressing normal tissues. Cellular therapy of cancer will need continued preclinical evaluation as well as carefully designed clinical trials addressing the various issues. For these challenges to be fully assessed, and for progression to a widely used, effective and safe therapy, development as cooperative groups is an appropriate way forward.

Published
2010

40. Four cell-secreted cytokines act synergistically to maintain long term proliferation of human B cell lines in vitro

Author

Abken H, Juliane Fluck, and Willecke K

Subjects
B-Lymphocytes, Base Sequence, Interleukin-6, Tumor Necrosis Factor-alpha, Molecular Sequence Data, Immunology, Receptors, Interleukin-1, Receptors, Cell Surface, Oligonucleotides, Antisense, Lymphocyte Activation, Receptors, Interleukin-6, Receptors, Tumor Necrosis Factor, Cell Line, Humans, Immunology and Allergy, Receptors, Immunologic, Lymphotoxin-alpha, Interleukin-1
Abstract

Autocrine production of growth factors is thought to be an essential element in the development of hemopoietic tumors in vivo. Tumor-derived cell lines frequently show this capability in vitro. It is not understood how autonomous growth in vitro is maintained by lymphoid cell lines that are not of tumorigenic origin. We have previously established human B cell clones that proliferate in serum-free media with unlimited potential. However, the cells need a critical density for continuous growth. Culture supernatant conditioned by these cell lines sustained proliferation even in low density cultures. All B cell clones analyzed were found to secrete the cytokines IL-1 alpha, IL-6, TNF-alpha, and TNF-beta whereas no activity of IL-2, IL-4, low m. w.-B cell growth factor, CSF, or IFN-gamma was recorded. In low density cultures supplemented with rIL-1 alpha, +/- IL-6, +/- TNF-alpha, and +/- TNF-beta together, B cell proliferation is maintained to the same extent as with conditioned medium. Addition of anti-sense oligonucleotides directed to the mRNA of IL-1 alpha, IL-6, and TNF-alpha, respectively, resulted in growth arrest and cell death. This effect could be prevented by supplementation with these cytokines. Scatchard plot analyses and internalization studies revealed that the cells express on their surface high affinity receptors for IL-1 alpha, IL-6, and TNF, respectively, and internalize the cytokines from the supernatant. These results demonstrate that (i) autonomous growth of immortalized B cells is maintained by secretion and reinternalization of IL-1 alpha, IL-6, TNF-alpha, and TNF-beta, (ii) these cytokines act in a synergistic fashion, and (iii) autocrine growth stimulation of human B cells in vitro does not necessarily represent their tumorigenic potential in vivo.

Published
1992

42. Rational development of high-affinity T-cell receptor-like antibodies

Author

Stewart-Jones, G, Wadle, A, Hombach, A, Shenderov, E, Held, G, Fischer, E, Kleber, S, Stenner-Liewen, F, Bauer, S, McMichael, A, Knuth, A, Abken, H, Hombach, A A, Cerundolo, V, Jones, E Y, Renner, C, and University of Zurich

Subjects
1000 Multidisciplinary, 10032 Clinic for Oncology and Hematology, 610 Medicine & health
Published
2009
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43. T cell activation by antibody-like immunoreceptors

Author

Hombach, A.A., Schildgen, V., Heuser, C., Finnern, R., Gilham, D.E., Abken, H., and Publica

Abstract

Recombinant TCRs confer specificity to T cells and trigger their activation. Receptors with Ab-derived binding domains have the advantages of MHC-independent Ag recognition and of targeting a variety of chemically different molecules. We explored the impact of the position of a defined epitope within the target molecule on the efficacy of receptor-mediated T cell activation. T cells were grafted with recombinant immunoreceptors that recognize either the membrane distal N or the proximal A3 domain of carcinoembryonic Ag (CEA). Upon binding to isolated, solid-phase immobilized CEA, receptor-mediated T cell activation correlates with the binding efficiency, irrespectively, of the epitope position. Upon binding to CEA expressed on the cell membrane, in contrast, the A3 epitope mediates more efficiently T cell activation than the N epitope, although the N epitope is bound with higher affinity. The CEA N epitope when expressed in a more membrane proximal position, however, ac tivated receptor grafted T cells with higher efficiency than in the distal position. The position of the targeted epitope within the molecule obviously has major impact on the efficacy of T cell activation independently of the binding efficiency of the immunoreceptor.

Published
2007

46. T cells redirected by a chimeric antigen receptor efficiently control Hepatitis B Virus replication in an immunocompetent mouse model

Author

Krebs, K, primary, Böttinger, N, additional, Huang, LR, additional, Chmielewski, M, additional, Arzberger, S, additional, Gasteiger, G, additional, Bohne, F, additional, Aichler, M, additional, Uckert, W, additional, Abken, H, additional, Heikenwälder, M, additional, Knolle, P, additional, and Protzer, U, additional

Published
2014
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49. 340 T CELLS REDIRECTED BY A CHIMERIC ANTIGEN RECEPTOR RECOGNIZING HBsAg EFFICIENTLY CONTROL HBV IN VIVO IN TRANSGENIC MICE

Author

Krebs, K., primary, Böttinger, N., additional, Huang, L.-R., additional, Chmielewski, M., additional, Arzberger, S., additional, Gasteiger, G., additional, Schmitt, E., additional, Bohne, F., additional, Aichler, M., additional, Uckert, W., additional, Abken, H., additional, Heikenwälder, M., additional, Knolle, P., additional, and Protzer, U., additional

Published
2013
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