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Lan Y, Moustafa M, Knoll M, et al. Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell. 2021;39(10):1388-1403.e10doi: 10.1016/j.ccell.2021.08.008.
Lan, Y., Moustafa, M., Knoll, M., Xu, C., Furkel, J., Lazorchak, A., Yeung, T. L., Hasheminasab, S. M., Jenkins, M. H., Meister, S., Yu, H., Schlegel, J., Marelli, B., Tang, Z., Qin, G., Klein, C., Qi, J., Zhou, C., Locke, G., Krunic, D., Derner, M. G., Schwager, C., Fontana, R. E., Kriegsmann, K., Jiang, F., Rein, K., Kriegsmann, M., Debus, J., Lo, K. M., & Abdollahi, A. (2021). Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer cell, 39(10), 1388-1403.e10. https://doi.org/10.1016/j.ccell.2021.08.008
Lan, Yan, et al. "Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion." Cancer cell vol. 39,10 (2021): 1388-1403.e10. doi: https://doi.org/10.1016/j.ccell.2021.08.008
Lan Y, Moustafa M, Knoll M, Xu C, Furkel J, Lazorchak A, Yeung TL, Hasheminasab SM, Jenkins MH, Meister S, Yu H, Schlegel J, Marelli B, Tang Z, Qin G, Klein C, Qi J, Zhou C, Locke G, Krunic D, Derner MG, Schwager C, Fontana RE, Kriegsmann K, Jiang F, Rein K, Kriegsmann M, Debus J, Lo KM, Abdollahi A. Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell. 2021 Oct 11;39(10):1388-1403.e10. doi: 10.1016/j.ccell.2021.08.008. Epub 2021 Sep 09. PMID: 34506739.
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Cancer Cell. 2021 Oct 11;39(10):1388-1403.e10. doi: 10.1016/j.ccell.2021.08.008. Epub 2021 Sep 09.

Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion.

Cancer cell

Yan Lan, Mahmoud Moustafa, Maximilian Knoll, Chunxiao Xu, Jennifer Furkel, Adam Lazorchak, Tsz-Lun Yeung, Sayed-Mohammad Hasheminasab, Molly H Jenkins, Sarah Meister, Huakui Yu, Julian Schlegel, Bo Marelli, Zili Tang, Guozhong Qin, Carmen Klein, Jin Qi, Cheng Zhou, George Locke, Damir Krunic, Melissa G Derner, Christian Schwager, Rachel E Fontana, Katharina Kriegsmann, Feng Jiang, Katrin Rein, Mark Kriegsmann, Juergen Debus, Kin-Ming Lo, Amir Abdollahi

Affiliations

  1. Department of TIP OIO, EMD Serono Research & Development Institute, 45 Middlesex Turnpike, Billerica, MA 01821, USA; an affiliate of Merck KGaA, Darmstadt, Germany. Electronic address: [email protected].
  2. German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Divisions of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; CCU Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; Department of Clinical Pathology, Suez Canal University, Ismailia 41522, Egypt.
  3. German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Divisions of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; CCU Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany.
  4. Department of TIP OIO, EMD Serono Research & Development Institute, 45 Middlesex Turnpike, Billerica, MA 01821, USA; an affiliate of Merck KGaA, Darmstadt, Germany.
  5. German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Divisions of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; CCU Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, Charité Universitätsmedizin, Berlin, Germany.
  6. German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Divisions of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; CCU Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  7. Department of Translational Medicine, EMD Serono Research & Development Institute, Billerica, MA 01821, USA; an affiliate of Merck KGaA, Darmstadt, Germany.
  8. Light Microscopy Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  9. Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany.
  10. Department of Pathology, Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany.
  11. German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Divisions of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany; CCU Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany. Electronic address: [email protected].

PMID: 34506739 DOI: 10.1016/j.ccell.2021.08.008

Abstract

Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: PD-L1; TGF-β; abscopal effect; compartmental targeting; immune evasion; immune therapy; lung fibrosis; radiotherapy; tumor microenvironment; tumor vaccination

Conflict of interest statement

Declaration of interests Y.L., C.X., T.-L.Y., M.H.J., H.Y., B.M., G.Q., J.Q., G.L., M.G.D., F.J., and K.-M.L. are all employees of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA

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