SFB 685:  Immunotherapy: Molecular Basis and Clinical Application

• Subject Area: Medicine ; Biology
• Term: from 2005 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 13799719

• Final Report Year: 2017

Final Report Abstract

At the time the SFB 685 started in 2004, cancer immunotherapy was widely considered as a kind of exotic field not expected to lead to something useful in cancer therapy. The group of scientists gathering to start an SFB in this field belonged to a minority still following Paul Ehrlich’s hypothesis that the immune system somehow can act against cancer. Now, in 2017, cancer immunotherapy is a prominent area in the cancer field, thanks to the success of checkpoint inhibition, and is rapidly growing and gaining impact on standard cancer therapies in an increasing number of entities. The SFB 685 has not initiated this revolution but we are proud to have contributed significantly to its scientific basis, and to have prepared the ground for new therapy approaches that are more specific and might help those patients not responding to checkpoint inhibition. These are still the majority of all cancer patients. The program of the SFB 685 called for translation of molecular basic research into clinical application. Indeed, this avenue has been followed, and several clinical trials have been performed or are underway at the conclusion of the SFB. These clinical studies are all run and financed externally, but SFB members and SFB knowledge have been instrumental in their realization. Some have been pursued by spin-offs at the University, others at academic levels, covering peptide and mRNA vaccinations, antibody therapies and adoptive cell transfer. New phase I/II trials are in preparation for 2018, based on the experiences gained so far, and with the promise of being more efficient. On the basic side, the SFB was successful in several areas: HLA ligandomics, senescence, inflammation, innate immunity, immunoinformatics, recombinant antibodies, immunoimaging, RNAi-screening, immunomonitoring, signal transduction, antimicrobial immunity. The activities of the SFB 685 resulted in important structural achievements. First of all, the participation of Tübingen as one of the eight members in the German Cancer Consortium (DKTK) would not have been possible without this SFB. Tübingen is leading the DKTK cancer immunotherapy program. During the course of the SFB, a further spin-off, Synimmune, was founded by SFB members, and is now running a phase I clinical trial with a function-improved FLT3-antibody in AML patients. A new kinase inhibitor, Skepinone, is in preparation for a first clinical trial in hepatocellular cancer. Two new SFB initiatives are in active preparation by former SFB 685 members: Dormant Cancer (Martin Röcken) and Multimodal in vivo Imaging (Bernd Pichler). Two excellence clusters that have reached the 2018 round are led by former SFB 685 members: iFIT (Image-Guided and Functionally-Instructed Tumor Therapies) by Lars Zender and CMFI (Controlling Microbes to Fight Infections) by Andreas Peschel.

Publications

• Mutual activation of natural killer cells and monocytes mediated by NKp80-AICL interaction. Nat Immunol. 7(12):1334-42, 2006
  Welte S, Kuttruff S, Waldhauer I, Steinle A
  (See online at https://doi.org/10.1038/ni1402)
• Peptides made to order. Immunity 25(5):693-5, 2006
  Rammensee HG
  (See online at https://doi.org/10.1016/j.immuni.2006.10.008)
• Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses. Proc Natl Acad Sci U S A. 103(13):5042-7, 2006
  Osterloh P, Linkemann K, Tenzer S, Rammensee HG, Radsak MP, Busch DH, Schild H
  (See online at https://doi.org/10.1073/pnas.0509256103)
• Adenovirus reshapes the surface of ist cellular receptor CD46. Nat. Struct. Mol. Biol. 14:164-66, 2007
  Persson BD, Reiter D, Marttila M, Mei YF, Casasnovas JM, Arnberg N, Stehle T
  (See online at https://doi.org/10.1038/nsmb1190)
• HLA-G expression defines a novel regulatory T cell subset present in human peripheral blood and sites of inflammation. Blood 110:568-577, 2007
  Feger U, Tolosa E, Huang YH, Waschbisch A, Biedermann T, Melms A, Wiendl H
  (See online at https://doi.org/10.1182/blood-2006-11-057125)
• Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest. 117(11):3576-82, 2007
  Wahlström J, Dengjel J, Persson B, Duyar H, Rammensee HG, Stevanović S, Eklund A, Weissert R, Grunewald J
  (See online at https://doi.org/10.1172/jci32401)
• TNFR1 Signaling and IFN-gamma Signaling Determine whether T Cells Induce Tumor Dormancy or Promote Multistage Carcinogenesis. Cancer Cell 13: 507-18, 2008
  Müller-Hermelink N, Braumüller H, Pichler B, Wieder T, Mailhammer R, Schaak K, Ghoreschi K, Yazdi A, Haubner R, Sander CA, Mocikat R, Schwaiger M, Förster I, Huss R, Weber WA, Kneilling M, Röcken M
  (See online at https://doi.org/10.1016/j.ccr.2008.04.001)
• Direct crosstalk between mast cell-TNF and TNFR1-expressing endothelia mediates local tissue inflammation. Blood 114: 1696-706, 2009
  Kneilling M, Mailhammer R, Hültner L, Schönberger T, Fuchs K, Schaller M, Bukala D, Massberg S, Sander CA, Braumüller H, Eichner M, Maier KL, Hallmann R, Pichler BJ, Haubner R, Gawaz M, Pfeffer K, Biedermann T, Röcken M
  (See online at https://doi.org/10.1182/blood-2008-11-187682)
• Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer 9(6):445-52, 2009
  Löb S, Königsrainer A, Rammensee HG, Opelz G, Terness P
  (See online at https://doi.org/10.1038/nrc2639)
• NKp80 defines and stimulates a reactive subset of CD8 T cells. Blood 113(2):358-69, 2009
  Kuttruff S, Koch S, Kelp A, Pawelec G, Rammensee HG, Steinle A
  (See online at https://doi.org/10.1182/blood-2008-03-145615)
• Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116(20):4360-4367, 2010
  Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM, Mohty M, Or R, Maschan M, Schumm M, Hamprecht K, Handgretinger R, Lang P, Einsele H
  (See online at https://doi.org/10.1182/blood-2010-01-262089)
• Interaction of C-type lectin-like receptors NKp65 and KACL facilitates dedicated immune recognition of human keratinocytes. Proc Natl Acad Sci USA 107(11):5100-5, 2010
  Spreu J, Kuttruff S, Stejfova V, Dennehy KM, Schittek B, Steinle A
  (See online at https://doi.org/10.1073/pnas.0913108107)
• Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci U S A. 107(19):8772- 877, 2010
  Peyrin-Biroulet L, Beisner J, Wang G, Nuding S, Oommen ST, Kelly D, Parmentier-Decrucq E, Dessein R, Merour E, Chavatte P, Grandjean T, Bressenot A, Desreumaux P, Colombel JF, Desvergne B, Stange EF, Wehkamp J, Chamaillard M
  (See online at https://doi.org/10.1073/pnas.0905745107)
• The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol. 6(5):280-9, 2010
  Muñoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M
  (See online at https://doi.org/10.1038/nrrheum.2010.46)
• Reduction of disulphide bonds unmasks potent antimicrobial activity of human betadefensin 1. Nature 469(7330):419-42, 2011
  Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J, Buchner J, Schaller M, Stange EF, Wehkamp J
  (See online at https://doi.org/10.1038/nature09674)
• The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis. Nat Med. 17:105-109, 2011
  Nilsson EC, Storm RJ, Bauer J, Johansson SM, Lookene A, Angström J, Hedenström M, Eriksson TL, Frängsmyr L, Rinaldi S, Willison HJ, Domellöf FP, Stehle T, Arnberg N
  (See online at https://doi.org/10.1038/nm.2267)
• Cleavage of annexin A1 by ADAM10 during secondary necrosis generates a monocytic "find-me" signal. J Immunol. 188(1):135-45, 2012
  Blume KE, Soeroes S, Keppeler H, Stevanovic S, Kretschmer D, Rautenberg M, Wesselborg S, Lauber K
  (See online at https://doi.org/10.4049/jimmunol.1004073)
• IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity 37(6):998-1008, 2012
  Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I
  (See online at https://doi.org/10.1016/j.immuni.2012.08.023)
• Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 18(8):1254-61, 2012
  Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, Hilf N, Schoor O, Fritsche J, Mahr A, Maurer D, Vass V, Trautwein C, Lewandrowski P, Flohr C, Pohla H, Stanczak JJ, Bronte V, Mandruzzato S, Biedermann T, Pawelec G, Derhovanessian E, Yamagishi H, Miki T, Hongo F, Takaha N, Hirakawa K, Tanaka H, Stevanovic S, Frisch J, Mayer-Mokler A, Kirner A, Rammensee HG, Reinhardt C, Singh-Jasuja H
  (See online at https://doi.org/10.1038/nm.2883)
• ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Nat Med. 18(1):128-134, 2012
  Hoetzenecker K, Wölbing F, Bruck J, Teske A, Valtcheva N, Fuchs K, Kneilling M, Park JH, Kim KH, Kim KW, Hoffmann P, Krenn C, Hai T, Ghoreschi K, Biedermann T, Röcken M
  (See online at https://doi.org/10.1038/nm.2557)
• T Cell Assays and MIATA: The Essential Minimum for Maximum Impact. Immunity 37:1-2, 2012
  Britten CM, Janetzki S, Butterfield LH, Ferrari G, Gouttefangeas C, Huber C, Kalos M, Levitsky HI, Maecker HT, Melief CJM, O’Donnell-Tormey J, Odunsi K, Old LJ, Ottenhoff THM, Ottensmeier C, Pawelec G, Roederer M, Roep BO, Romero P, van der Burg SH, Walter S, Hoos A, Davis MM
  (See online at https://doi.org/10.1016/j.immuni.2012.07.010)
• Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nat Commun. 4:2039, 2013
  Adamopoulou E, Tenzer S, Hillen N, Klug P, Rota IA, Tietz S, Gebhardt M, Stevanovic S, Schild H, Tolosa E, Melms A, Stoeckle C
  (See online at https://doi.org/10.1038/ncomms3039)
• T-helper-1-cell cytokines drive cancer into senescence. Nature 494(7437):361-5, 2013
  Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, Ranta F, Ullrich S, Mocikat R, Braungart K, Mehra T, Fehrenbacher B, Berdel J, Niessner H, Meier F, van den Broek M, Häring HU, Handgretinger R, Quintanilla-Martinez L, Fend F, Pesic M, Bauer J, Zender L, Schaller M, Schulze-Osthoff K, Röcken M
  (See online at https://doi.org/10.1038/nature11824)
• The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 122(7):1192-202, 2013
  Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P
  (See online at https://doi.org/10.1182/blood-2013-03-484642)
• The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol. 31(10):880-2, 2013
  Britten CM, Singh-Jasuja H, Flamion B, Hoos A, Huber C, Kallen KJ, Khleif SN, Kreiter S, Nielsen M, Rammensee HG, Sahin U, Hinz T, Kalinke U
  (See online at https://doi.org/10.1038/nbt.2708)
• Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515(7528):577-81, 2014
  Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD
  (See online at https://doi.org/10.1038/nature13988)
• Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity 41(5):762-775, 2014
  Skabytska Y, Wölbing F, Günther C, Köberle M, Kaesler S, Chen KM, Guenova E, Demircioglu D, Kempf WE, Volz T, Rammensee HG, Schaller M, Röcken M, Götz F, Biedermann T
  (See online at https://doi.org/10.1016/j.immuni.2014.10.009)
• In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20(10):1138-46, 2014
  Rudalska R, Dauch D, Longerich T, McJunkin K, Wuestefeld T, Kang TW, Hohmeyer A, Pesic M, Leibold J, von Thun A, Schirmacher P, Zuber J, Weiss KH, Powers S, Malek NP, Eilers M, Sipos B, Lowe SW, Geffers R, Laufer S, Zender L
  (See online at https://doi.org/10.1038/nm.3679)
• 64Cu antibody-targeting of the T-cell receptor and subsequent internalization enables in vivo tracking of lymphocytes by PET. Proc Natl Acad Sci U S A 112: 1161-6, 2015
  Griessinger CM, Maurer A, Kesenheimer C, Kehlbach R, Reischl G, Ehrlichmann W, Bukala D, Harant M, Cay F, Brück J, Nordin R, Kohlhofer U, Rammensee HG, Quintanilla-Martinez L, Schaller M, Röcken M, Pichler BJ, Kneilling M
  (See online at https://doi.org/10.1073/pnas.1418391112)
• Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood 125(12): 1986-1994, 2015
  Feucht J, Opherk K, Lang P, Kayser S, Hartl L, Bethge W, Matthes-Martin S, Bader P, Albert MH, Maecker-Kolhoff B, Greil J, Einsele H, Schlegel PG, Schuster FR, Kremens B, Rossig C, Gruhn B, Handgretinger R, Feuchtinger T
  (See online at https://doi.org/10.1182/blood-2014-06-573725)
• Dipeptides catalyze rapid peptide exchange on MHC class I molecules. Proc Natl Acad Sci U S A. 112(1):202-7, 2015
  Saini SK, Schuster H, Ramnarayan VR, Rammensee HG, Stevanović S, Springer S
  (See online at https://doi.org/10.1073/pnas.1418690112)
• High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates. Blood. 126(1):76-9, 2015
  Bonzheim I, Giese S, Deuter C, Süsskind D, Zierhut M, Waizel M, Szurman P, Federmann B, Schmidt J, Quintanilla-Martinez L, Coupland SE, Bartz-Schmidt KU, Fend F
  (See online at https://doi.org/10.1182/blood-2015-01-620518)
• HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL). Proc Natl Acad Sci USA. 112:E166-175, 2015
  Kowalewski DJ, Schuster H, Backert L, Berlin C, Kahn S, Kanz L, Salih HR, Rammensee HG, Stevanovic S, Stickel JS
  (See online at https://doi.org/10.1073/pnas.1416389112)
• Thinking outside the gate: single-cell assessments in multiple dimensions. Immunity 42:591-2, 2015
  Kvistborg P, Gouttefangeas C, Aghaeepour N, Cazaly A, Chattopadhyay PK, Chan C, Eckl J, Finak G, Hadrup SR, Maecker HT, Maurer D, Mosmann T, Qiu P, Scheuermann RH, Welters MJP, Ferrari G, Brinkman RR, Britten CM
  (See online at https://doi.org/10.1016/j.immuni.2015.04.006)
• A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med. 22(7):744-53, 2016
  Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, Hohmeyer A, Imbeaud S, Yevsa T, Hoenicke L, Pantsar T, Bozko P, Malek NP, Longerich T, Laufer S, Poso A, Zucman-Rossi J, Eilers M, Zender L
  (See online at https://doi.org/10.1038/nm.4107)
• Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. Cancer Cell 30(4):533-547, 2016
  Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, Medina-Echeverz J, Longerich T, Forgues M, Reisinger F, Heikenwalder M, Wang XW, Zender L, Greten TF
  (See online at https://doi.org/10.1016/j.ccell.2016.09.003)
• Exploitation of Natural Killer (NK) cells for the treatment of acute leukemia. Blood 127(26):3341-9, 2016
  Handgretinger R, Lang P, André MC
  (See online at https://doi.org/10.1182/blood-2015-12-629055)
• Graft versus self (GvS) against T-cell autoantigens is a mechanism of graft-host interaction. Proc Natl Acad Sci U S A. 113(48):13827-13832, 2016
  Mirza N, Zierhut M, Korn A, Bornemann A, Vogel W, Schmid-Horch B, Bethge WA, Stevanović S, Salih HR, Kanz L, Rammensee HG, Haen SP
  (See online at https://doi.org/10.1073/pnas.1609118113)
• OpenMS: a flexible open-source software platform for mass spectrometry data analysis. Nature Methods 13(9):741-748, 2016
  Röst, HL, Sachsenberg T, Aiche S, Bielow C, Weisser H, Aicheler F, Andreotti S, Ehrlich H, Gutenbrunner P, Kenar E, Liang X, Nahnsen S, Nilse L, Pfeuffer J, Rosenberger G, Rurik M, Schmitt U, Veit J, Walzer M, Wojnar D, Wolski WE, Schilling O, Choudhary JS, Malmström L, Aebersold R, Reinert K, Kohlbacher O
  (See online at https://doi.org/10.1038/nmeth.3959)
• The immunopeptidomic landscape of ovarian carcinomas. Proc Natl Acad Sci U S A. 114(46):E9942-E9951, 2017
  Schuster H, Peper JK, Bösmüller HC, Röhle K, Backert L, BilichT, Ney B, Löffler MW, Kowalewski DJ, Trautwein N, Rabsteyn A, Engler T, Braun S, Haen SP, Walz JS, Schmid-Horch B, Brucker SY, Wallwiener D, Kohlbacher O, Fend F, Rammensee HG, Stevanović S, Staebler A, Wagner P
  (See online at https://doi.org/10.1073/pnas.1707658114)