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DOI: 10.1055/s-0042-110216
Chimäre antigenspezifische T-Lymphozyten und natürliche Killerzellen für die Krebsimmuntherapie
Publication History
Publication Date:
26 August 2016 (online)
Zusammenfassung
Mehr als 20 Jahre nach den ersten Versuchen, die gezeigt haben, dass T-Lymphozyten mittels Gentransfer eines chimären Antigenrezeptors (CAR) künstlich mit einer Spezifität gegen Tumorantigene ausgerüstet werden können, erzielt dieser Ansatz bahnbrechende therapeutische Erfolge bei Patienten mit B-Zell-Leukämien unter Verwendung von Anti-CD19-CAR-T-Zellen. Die langanhaltende klinische Remission in Patienten mit ansonsten überaus schlechter Prognose ist der 2. und 3. Generation chimärer Antigenrezeptoren geschuldet, die nun die für eine Expansion von T-Lymphozyten in vivo wichtige Kostimulation intrinsisch innerhalb des CAR vorhalten. Der große therapeutische Durchbruch in zuvor unheilbaren hämatologischen Erkrankungen hat zu einer Flut von neuen therapeutischen Ansätzen in einer Vielzahl von hämatologischen und soliden Tumoren geführt, bei denen diese neue Zelltherapie nun klinisch erprobt wird. Es bleibt abzuwarten, ob sich die guten klinischen Ergebnisse, die bei akuten lymphatischen Leukämien (B-ALL) erzielt wurden, auch auf andere hämatologische Erkrankungen und insbesondere auch auf solide Tumoren ausweiten lassen. Nichtsdestotrotz stehen für Patienten mit B-Zell-Leukämien, bei denen bisherige Standardtherapien – inklusive einer Stammzelltransplantation – versagt haben, heute neue Therapieoptionen zur Verfügung. Diese effizienten Therapieverfahren sollten möglichst zeitnah auch für Patienten in Deutschland zugängig gemacht werden. Die Einrichtungen für Transfusionsmedizin, Hämatologie und Onkologie sowie die nationalen und internationalen Aufsichtsbehörden sind gefragt, hier konstruktiv und mit Blick auf den klinischen Bedarf – jedoch ebenfalls die Sicherheit – der Patienten eine rasche Verfügbarkeit in Deutschland zu gewährleisten.
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Literatur
- 1 Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480: 480-489
- 2 Loren AW, Porter DL. Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant 2008; 41: 483-493
- 3 Pulsipher MA, Langholz B, Wall DA et al. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: A phase 3 Childrenʼs Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood 2014; 123: 2017-2025
- 4 Stanislawski T, Voss RH, Lotz C et al. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2001; 2: 962-970
- 5 Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013; 3: 388-398
- 6 Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-t-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 1989; 86: 10024-10028
- 7 Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 1991; 64: 891-901
- 8 Chmielewski M, Hombach AA, Abken H. Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells. Front Immunol 2013; 4: 371
- 9 Finney HM, Lawson AD, Bebbington CR et al. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol 1998; 161: 2791-2797
- 10 Hombach A, Wieczarkowiecz A, Marquardt T et al. Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. J Immunol 2001; 167: 6123-6131
- 11 Thistlethwaite F, Mansoor W, Gilham DE et al. Engineering T-cells with antibody-based chimeric receptors for effective cancer therapy. Curr Opin Mol Ther 2005; 7: 48-55
- 12 Hombach A, Abken H. Costimulation tunes tumor-specific activation of redirected T cells in adoptive immunotherapy. Cancer Immunol Immunother 2007; 56: 731-737
- 13 Hombach A, Sent D, Schneider C et al. T-cell activation by recombinant receptors: CD28 costimulation is required for interleukin 2 secretion and receptor-mediated T-cell proliferation but does not affect receptor-mediated target cell lysis. Cancer Res 2001; 61: 1976-1982
- 14 Kershaw MH, Westwood JA, Parker LL et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clinical Cancer Res 2006; 12: 6106-6115
- 15 Lamers CH, Sleijfer S, Vulto AG et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 2006; 24: e20-e22
- 16 Brentjens RJ, Riviere I, Park JH et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011; 118: 4817-4828
- 17 Porter DL, Levine BL, Kalos M et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365: 725-733
- 18 Kochenderfer JN, Dudley ME, Feldman SA et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2012; 119: 2709-2720
- 19 Kalos M, Levine BL, Porter DL et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3: 95ra73
- 20 Turtle CJ, Hanafi LA, Berger C et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016; 126: 2123-2138
- 21 Maude SL, Frey N, Shaw PA et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371: 1507-1517
- 22 Grupp SA, Kalos M, Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509-1518
- 23 Lee DW, Kochenderfer JN, Stetler-Stevenson M et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 2015; 385: 517-528
- 24 Brentjens RJ, Davila ML, Riviere I et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5: 177ra138
- 25 Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014; 6: 224ra225
- 26 Davila ML, Sadelain M. Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol 2016; 104: 6-17
- 27 Schuster SJ, Svoboda J, Dvivedy Nasta S et al. Sustained remissions following chimeric antigen receptor modified T cells directed against cCD9 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood 2015; 126: 183
- 28 Kochenderfer JN, Dudley ME, Kassim SH et al. Chemotherapy-refractory diffuse large b-cell lymphoma and indolent b-cell malignancies can be effectively treated with autologous t cells expressing an anti-cd19 chimeric antigen receptor. J Clin Oncol 2015; 33: 540-549
- 29 Turtle CJ, Berger C, Sommermeyer D et al. Anti-CD19 chimeric antigen receptor-modified T cell therapy for B cell non-hodgkin lymphoma and chronic lymphocytic leukemia: Fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes. Blood 2015; 126: 184
- 30 Porter DL, Hwang WT, Frey NV et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7: 303ra139
- 31 Maude SL, Barrett D, Teachey DT et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014; 20: 119-122
- 32 Winkler U, Jensen M, Manzke O et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999; 94: 2217-2224
- 33 Lee DW, Gardner R, Porter DL et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124: 188-195
- 34 Morgan RA, Yang JC, Kitano M et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010; 18: 843-851
- 35 Brentjens R, Yeh R, Bernal Y et al. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 2010; 18: 666-668
- 36 Gill S, June CH. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol Rev 2015; 263: 68-89
- 37 Suck G. Novel approaches using natural killer cells in cancer therapy. Semin Cancer Biol 2006; 16: 412-418
- 38 Suck G, Linn YC, Tonn T. Natural killer cells for therapy of leukemia. Transfus Med Hemother 2016; 43: 89-95
- 39 Brehm C, Huenecke S, Quaiser A et al. Il-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: concomitant results to a phase I/II study. PloS One 2011; 6: e27351
- 40 Suck G, Odendahl M, Nowakowska P et al. NK-92: An ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 2016; 65: 485-492
- 41 Tonn T, Becker S, Esser R et al. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J Hematother Stem Cell Res 2001; 10: 535-544
- 42 Tonn T, Seifried E. Natural killer cells for the treatment of malignancies. Transfus Med Hemother 2006; 2006: 144-149
- 43 Tonn T, Schwabe D, Klingemann HG et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 2013; 15: 1563-1570
- 44 Arai S, Meagher R, Swearingen M et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 2008; 10: 625-632
- 45 Müller T, Uherek C, Maki G et al. Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother 2008; 57: 411-423
- 46 Romanski A, Uherek C, Bug G et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. J Cell Mol Med 2016; 20: 1287-1294
- 47 Uherek C, Tonn T, Uherek B et al. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood 2002; 100: 1265-1273
- 48 Schonfeld K, Sahm C, Zhang C et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther 2015; 23: 330-338
- 49 Zhang C, Burger MC, Jennewein L et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Natl Cancer Inst 2015; 108 pii: djv375