Evolution von T-Zell Funktion in AML – Maßgeschneiderte Antikörper-basierte Immuntherapie mit dem Fokus konstitutive und erworbene Immunresistenzfaktoren zu überwinden.
Biochemie
Immunologie
Zusammenfassung der Projektergebnisse
Recent advances in immunotherapy, such as T-cell recruiting bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells, have confirmed the therapeutic potential of T cell-based approaches in treating malignant diseases. However, their implementation into acute myeloid leukemia (AML) treatment has not succeeded. Besides clonal heterogeneity and variable target antigen expression profiles, T cell-based therapies are hampered by the alteration of T cells through e.g. the upregulation of inhibitory receptors on AML cells, chronic antigen exposure, or the creation of an immunosuppressive microenvironment. By extensive characterization of T cells throughout the progression of AML, we revealed a signature of T cell dysfunction compared to healthy donor T cells, which evolved from senescence-like at initial diagnosis (ID) to exhaustionlike at the time of relapse (RL). T-cell dysfunction in ID and RL became even more evident through decreased BsAb-mediated cytotoxicity, proliferation, and metabolic fitness compared to complete remission samples. Furthermore, we demonstrated that TP53 aberrations in AML contribute to T-cell suppression by inducing a state of quiescence or senescence, which impairs their cytotoxic and proliferative potential. We evaluated the combination of BsAbs and costimulatory antibody constructs to counteract T-cell dysfunction. Indeed, we could show that costimulation of T-cells through 4-1BBL and OX40L enhances BsAb-mediated cytotoxicity and T cell proliferation. Another approach to counteract escape mechanisms led to the development of the Adapter CAR T cell platform, allowing simultaneous targeting of multiple antigens and the introduction of treatmentfree intervals to circumvent chronic stimulation-induced T-cell exhaustion.
Projektbezogene Publikationen (Auswahl)
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Evolving Exhaustion of T Cells during the Course of the Disease in AML Can be Abrogated By CD33 BiTE ® Construct Mediated Cytotoxicity. Blood, 138(Supplement 1), 1172-1172.
Kazerani, Pasikhani Maryam; Marcinek, Anetta; Brauchle, Bettina; Taylor, Jonathan Jonas; Domínguez, Moreno Helena; Solovey, Maria; Ziemann, Frank; Zieger, Nora; Terrasi, Andrea; Tast, Benjamin; Spiekermann, Karsten; Metzeler, Klaus H.; Straub, Tobias; Schotta, Gunnar; Kischel, Roman; Buecklein, Veit L. & Subklewe, Marion
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SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells. Journal of Hematology & Oncology, 14(1).
Tahk, Siret; Vick, Binje; Hiller, Björn; Schmitt, Saskia; Marcinek, Anetta; Perini, Enrico D.; Leutbecher, Alexandra; Augsberger, Christian; Reischer, Anna; Tast, Benjamin; Humpe, Andreas; Jeremias, Irmela; Subklewe, Marion; Fenn, Nadja C. & Hopfner, Karl-Peter
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Integrated multiomic approach for identification of novel immunotherapeutic targets in AML. Biomarker Research, 10(1).
Köhnke, Thomas; Liu, Xilong; Haubner, Sascha; Bücklein, Veit; Hänel, Gerulf; Krupka, Christina; Solis-Mezarino, Victor; Herzog, Franz & Subklewe, Marion
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T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals. Blood, 140(10), 1104-1118.
Philipp, Nora; Kazerani, Maryam; Nicholls, Alyssa; Vick, Binje; Wulf, Jan; Straub, Tobias; Scheurer, Michaela; Muth, Amelie; Hänel, Gerulf; Nixdorf, Daniel; Sponheimer, Monika; Ohlmeyer, Malte; Lacher, Sonja M.; Brauchle, Bettina; Marcinek, Anetta; Rohrbacher, Lisa; Leutbecher, Alexandra; Rejeski, Kai; Weigert, Oliver ... & Subklewe, Marion
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Uncovering the Enemy: Single-Cell Transcriptional Profiling of Measurable Residual Disease (MRD) Cells. Blood, 140(Supplement 1), 6321-6322.
Kazerani, Maryam; Wange, Lucas; Tast, Benjamin; Solovey, Maria; Nixdorf, Daniel; Rohrbacher, Lisa; Heitmüller, Christina; Koehnke, Thomas; Schnorfeil, Frauke; Grunwald, Victoria V.; Spiekermann, Karsten; Metzeler, Klaus H.; Hopfner, Karl-Peter; Enard, Wolfgang; Buecklein, Veit L. & Subklewe, Marion
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Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML. Leukemia, 37(6), 1298-1310.
Nixdorf, D.; Sponheimer, M.; Berghammer, D.; Engert, F.; Bader, U.; Philipp, N.; Kazerani, M.; Straub, T.; Rohrbacher, L.; Wange, L.; Dapa, S.; Atar, D.; Seitz, C. M.; Brandstetter, K.; Linder, A.; von Bergwelt, M.; Leonhardt, H.; Mittelstaet, J.; Kaiser, A. ... & Subklewe, M.
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CD33 BiTE® molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells. Cancer Immunology, Immunotherapy, 72(7), 2499-2512.
Marcinek, Anetta; Brauchle, Bettina; Rohrbacher, Lisa; Hänel, Gerulf; Philipp, Nora; Märkl, Florian; Strzalkowski, Thaddäus; Lacher, Sonja M.; Udiljak, Dragica; Spiekermann, Karsten; Theurich, Sebastian; Kobold, Sebastian; Kischel, Roman; James, John R.; Bücklein, Veit L. & Subklewe, Marion
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The Battle within: AML´s p53 Strategies to Evade T-Cell Attack. Blood, 142(Supplement 1), 1411-1411.
Winter, Lis; Pawlowsky, Lea; Marcinek, Anetta; Brauchle, Bettina; Muth, Amelie; Kazerani, Maryam; Petrera, Agnese; Kischel, Roman; Emhardt, Alica Joana; Rothenberg-Thurley, Maja; Dufour, Annika Maria; Spiekermann, Karsten; Andreeff, Michael; Daver, Naval; Buecklein, Veit L. & Subklewe, Marion
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Evolution of T-cell fitness through AML progression: enhanced bispecific T-cell engager-mediated function of bone marrow T cells at remission compared to initial diagnosis and relapse. Leukemia, 38(10), 2270-2275.
Kazerani, Maryam; Marcinek, Anetta; Philipp, Nora; Brauchle, Bettina; Taylor, Jonathan Jonas; Moreno, Helena Domínguez; Terrasi, Andrea; Tast, Benjamin; Rohrbacher, Lisa; Wang, Yingshuai; Warm, Maximilian; Emhardt, Alica-Joana; Magno, Giulia; Spiekermann, Karsten; Herold, Tobias; Straub, Tobias; Theurich, Sebastian; Schotta, Gunnar; Kischel, Roman ... & Subklewe, Marion
