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The Na laboratory (AG Immuno-Oncology) investigates protection strategies of the bone marrow niche and the restoration of immune competence after chemotherapy and allogeneic hematopoietic stem cell transplantation. Focus are cell therapeutic approaches, the optimization of adoptive T cell therapy and the implementation of B cell therapy. In order to better understand the effects of targeted therapies and immunotherapies, we are also pursuing a “next generation staging”, longitudinally and comprehensively monitoring dynamic modifications of the tumor, the tumor microenvironment and the immune system enforced by the chosen treatment.
I) We revealed secondary immune deficiencies in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Bone marrow niche damages with osteoblast loss have been associated with increased numbers of infiltrating donor T cells suggesting acute graft versus host disease and impaired B cell reconstitution. Even one year after alloHSCT, numbers of memory B cells were significantly reduced and B cells revealed a high apoptosis-susceptibility upon stimulation. We are interested in a) unravelling the mechanism of human bone marrow GvHD, b) studying long-term residency of memory B cells in the bone marrow, and c) the possibility to use “long-living” antigen-specific memory B and T cells residing in the bone marrow or other tissues for adoptive cell transfer in immunodeficient patients.
II) Adoptive T cell transfer (ATT) of antigen-specific T cells can be a remarkably efficient cancer therapy, but durable complete responses are rarely achieved in the treatment of solid tumors. Recent advances have widened the spectrum of therapeutics to be used in combination with ATT in order to overcome inhibitory mechanisms presented by solid tumors and their microenvironment. Their evaluation would greatly benefit from an in vivo monitoring tool allowing the detection of functional parameters of transferred T cells. We generated a transgenic mouse line BLITC (bioluminescence imaging of T cells) expressing an NFAT-dependent Click-beetle luciferase and a constitutive Renilla luciferase facilitating longitudinal in vivo studies on T cell activation and migration in various mouse models. We could demonstrate its suitability in two independent tumor models employing tumor-antigen mono-specific CD4+ and CD8+ T cells. Our BLI data demonstrated rapid tumor infiltration but suggested transient T cell activation to be causative for the failure to reject solid tumors, further emphasizing the importance of accessory treatments for ATT. In addition, the transfer of T cells involves the risk of adverse effects due to on-target off-tumor toxicity. Using a clinically relevant minor histocompatibility antigen (MiHA) H-Y tumor model, we monitored alloreactivity upon single MiHA mismatch in female -> male transfers in order to investigate on-target off-tumor toxicity. Using this bioluminescent reporter system we are currently testing treatment strategies for optimized T cell mediated cancer therapy. Further information
III) Currently, treatment decisions are typically made based on initial tumor and patient characteristics “at diagnosis”. However, dynamic therapy-induced remodeling in cancer patients remains largely neglected, although these changes may profoundly interfere with drug efficacy and tumor immune control. Hypothesizing that a better molecular and functional characterization of tumor and host properties in response to therapy will improve patient outcome by guiding informed cancer precision medicine, we propose a comprehensive screening of tumor, host and tumor/host interface parameters at various time-points during therapy. Starting with patients suffering from diffuse large B-cell lymphoma (DLBCL), we are establishing a comprehensive monitoring algorithm. We see great potential for a longitudinal (per individual) and horizontal (per cohort) scanning to provide critical individualized information for tailored treatment approaches (combination, patient selection, novel targets).
- Prof. Carmen Scheibenbogen, Institute of Immunology, Charité
- Prof. Andreas Thiel, Berlin-Brandenburg Centrum for Regenerative Medicine
- Prof. Hans-Dieter Volk, Berlin-Brandenburg Centrum for Regenerative Medicine
- Prof. Anita Kramer, Universität Erlangen
- Prof. Thomas Blankenstein, Max-Delbrück-Centrum Prof. Wolfgang Uckert, Max-Delbrück-Centrum
- PD Dr. Korinna Jöhrens, Institute of Pathology, Charité Prof. Marcel van den Brink, Memorial Sloan-Kettering Cancer Center, New York, USA
- Prof. Alexander Scheffold, Deutsches Rheumaforschungszentrum Prof. Chiara Romagnani, Deutsches Rheuma-Forschungszentrum
- Prof. Nina Babel, Berlin-Brandenburg Centrum for Regenerative Medicine
- Prof. Petra Reinke, Berlin-Brandenburg Centrum for Regenerative Medicine
- Prof. Armin Gerbitz, Hematology, Oncology and Tumor Immunology
- Prof. Clemens Schmitt, Hematology, Oncology and Tumor Immunology, Charité
- PD Dr. Olaf Penack, Hematology, Oncology and Tumor Immunology, Charité
- Prof. Wolfgang Blau, Hematology, Oncology and Tumor Immunology, Charité
Martin Szyska M, Na IK. Bone marrow GvHD after allogeneic hematopoietic stem cell transplantation. Frontiers in Immunology 2016 Mar 30;7:118.
Mensen A, Oh Y, Becker SC, Hemmati PG, Jehn C, Westermann J, Szyska M, Göldner H, Dörken B, Scheibenbogen C, Arnold R, Na IK. Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2015 Nov;21(11):1895-906.
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, Spoerl S, Ditschkowski M, Ecsedi M, Sockel K, Ayuk F, Ajib S, de Fontbrune FS, Na IK, Penter L, Holtick U, Wolf D, Schuler E, Meyer E, Apostolova P, Bertz H, Marks R, Lübbert M, Wäsch R, Scheid C, Stölzel F, Ordemann R, Bug G, Kobbe G, Negrin R, Brune M, Spyridonidis A, Schmitt-Gräff A, van der Velden W, Huls G, Mielke S, Grigoleit GU, Kuball J, Flynn R, Ihorst G, Du J, Blazar BR, Arnold R, Kröger N, Passweg J, Halter J, Socié G, Beelen D, Peschel C, Neubauer A, Finke J, Duyster J, von Bubnoff N. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015 Oct;29(10):2062-8.
Mensen A, Jöhrens K, Anagnostopoulos I, Demski S, Oey M, Stroux A, Hemmati P, Westermann J, Blau O, Wittenbecher F, Movassaghi K, Szyska M, Thomas S, Dörken B, Scheibenbogen C, Arnold R, Na IK. Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT. Blood 2014 Aug 7;124(6):963-72.
Mensen A, Ochs C, Stroux A, Wittenbecher F, Szyska M, Imberti L, Fillatreau S, Uharek L, Arnold R, Dörken B, Thiel A, Scheibenbogen C, Na IK. Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation. J Transl Med. 2013 Aug 14;11:188.
Ghosh A, Holland AM, Dogan Y, Yim NL, Rao UK, Young LF, West ML, Singer NV, Lee H, Na IK, Tsai JJ, Jenq RR, Penack O, Hanash AM, Lezcano C, Murphy GF, Liu C, Sadelain M, Sauer MG, Sant'angelo D, van den Brink MR. PLZF confers effector functions to donor T cells that preserve graft-versus-tumor effects while attenuating GVHD. Cancer Res. 2013 Aug 1;73(15):4687-96.
Na IK, Wittenbecher F, Dziubianau M, Herholz A, Mensen A, Kunkel D, Blau O, Blau I, Thiel E, Uharek L, Scheibenbogen C, Rieger K, Thiel A. Rabbit antithymocyte globulin (thymoglobulin) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients. Haematologica 2013 Jan;98(1):23-30.
Hanash AM, Kappel LW, Yim NL, Nejat RA, Goldberg GL, Smith OM, Rao UK, Dykstra L, Na IK, Holland AM, Dudakov JA, Liu C, Murphy GF, Leonard WJ, Heller G, van den Brink MR. Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL. Blood 2011 Jul 14;118(2):446-55.
Na IK, Markley JC, Tsai JJ, Yim NL, Beattie BJ, Klose AD, Holland AM, Ghosh A, Rao UK, Stephan MT, Serganova I, Santos EB, Brentjens RJ, Blasberg RG, Sadelain M, van den Brink MR. Concurrent visualization of trafficking, expansion, and activation of T lymphocytes and T-cell precursors in vivo. Blood. 2010 Sep 16;116(11):e18-25.
Na IK, Lu SX, Yim NL, Goldberg GL, Tsai J, Rao U, Smith OM, King CG, Suh D, Hirschhorn-Cymerman D, Palomba L, Penack O, Holland AM, Jenq RR, Ghosh A, Tran H, Merghoub T, Liu C, Sempowski GD, Ventevogel M, Beauchemin N, van den Brink MR. The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease. J Clin Invest. 2010 Jan;120(1):343-56.