Stefan Grote1, Frank Traub2, Joerg Mittelstaet3, Christian Seitz1, Andrew Kaiser3, Rupert Handgretinger1, Sabine Schleicher1. 1. Department of Hematology and Oncology, University Hospital Tuebingen, Children's Hospital, 72076 Tuebingen, Germany. 2. Department of Orthopedics and Traumatology, University Medical Center Mainz, Johannes Gutenberg University Mainz, 55131 Mainz, Germany. 3. Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany.
Abstract
BACKGROUND: Since metastatic spreading of solid tumor cells often leads to a fatal outcome for most cancer patients, new approaches for patient-individualized, targeted immunotherapy are urgently needed. METHODS: Here, we established cell lines from four bone metastases of different tumor entities. We assessed AdCAR NK-92-mediated cytotoxicity in vitro in standard cytotoxicity assays as well as 3D spheroid models Results: AdCAR-engineered NK-92 cells successfully demonstrated distinct and specific cytotoxic potential targeting different tumor antigens expressed on cell lines established from bone metastases of mammary, renal cell and colorectal carcinoma as well as melanomas. In that process AdCAR NK-92 cells produced a multitude of NK effector molecules as well as pro inflammatory cytokines. Furthermore, AdCAR NK-92 showed increased cytotoxicity in 3D spheroid models which can recapitulate in vivo architecture, thereby bridging the gap between in vitro and in vivo models. CONCLUSIONS: AdCAR NK-92 cells may provide an interesting and promising "off-the-shelf" cellular product for the targeted therapy of cancers metastasizing to the bone, while utilization of clinically approved, therapeutic antibodies, as exchangeable adapter molecules can facilitate quick clinical translation.
BACKGROUND: Since metastatic spreading of solid tumor cells often leads to a fatal outcome for most cancerpatients, new approaches for patient-individualized, targeted immunotherapy are urgently needed. METHODS: Here, we established cell lines from four bone metastases of different tumor entities. We assessed AdCAR NK-92-mediated cytotoxicity in vitro in standard cytotoxicity assays as well as 3D spheroid models Results:AdCAR-engineered NK-92 cells successfully demonstrated distinct and specific cytotoxic potential targeting different tumor antigens expressed on cell lines established from bone metastases of mammary, renal cell and colorectal carcinoma as well as melanomas. In that process AdCAR NK-92 cells produced a multitude of NK effector molecules as well as pro inflammatory cytokines. Furthermore, AdCAR NK-92 showed increased cytotoxicity in 3D spheroid models which can recapitulate in vivo architecture, thereby bridging the gap between in vitro and in vivo models. CONCLUSIONS:AdCAR NK-92 cells may provide an interesting and promising "off-the-shelf" cellular product for the targeted therapy of cancers metastasizing to the bone, while utilization of clinically approved, therapeutic antibodies, as exchangeable adapter molecules can facilitate quick clinical translation.
Entities:
Keywords:
NK-92; adapter; bone metastasis; chimeric antigen receptor; solid tumors
Authors: Enli Liu; David Marin; Pinaki Banerjee; Homer A Macapinlac; Philip Thompson; Rafet Basar; Lucila Nassif Kerbauy; Bethany Overman; Peter Thall; Mecit Kaplan; Vandana Nandivada; Indresh Kaur; Ana Nunez Cortes; Kai Cao; May Daher; Chitra Hosing; Evan N Cohen; Partow Kebriaei; Rohtesh Mehta; Sattva Neelapu; Yago Nieto; Michael Wang; William Wierda; Michael Keating; Richard Champlin; Elizabeth J Shpall; Katayoun Rezvani Journal: N Engl J Med Date: 2020-02-06 Impact factor: 91.245
Authors: Lars Wallstabe; Claudia Göttlich; Lena C Nelke; Johanna Kühnemundt; Thomas Schwarz; Thomas Nerreter; Hermann Einsele; Heike Walles; Gudrun Dandekar; Sarah L Nietzer; Michael Hudecek Journal: JCI Insight Date: 2019-09-19
Authors: Shannon L Maude; Theodore W Laetsch; Jochen Buechner; Susana Rives; Michael Boyer; Henrique Bittencourt; Peter Bader; Michael R Verneris; Heather E Stefanski; Gary D Myers; Muna Qayed; Barbara De Moerloose; Hidefumi Hiramatsu; Krysta Schlis; Kara L Davis; Paul L Martin; Eneida R Nemecek; Gregory A Yanik; Christina Peters; Andre Baruchel; Nicolas Boissel; Francoise Mechinaud; Adriana Balduzzi; Joerg Krueger; Carl H June; Bruce L Levine; Patricia Wood; Tetiana Taran; Mimi Leung; Karen T Mueller; Yiyun Zhang; Kapildeb Sen; David Lebwohl; Michael A Pulsipher; Stephan A Grupp Journal: N Engl J Med Date: 2018-02-01 Impact factor: 91.245
Authors: Subhashis Sarkar; Michel van Gelder; Willy Noort; Yunping Xu; Kasper M A Rouschop; Richard Groen; Harry C Schouten; Marcel G J Tilanus; Wilfred T V Germeraad; Anton C M Martens; Gerard M J Bos; Lotte Wieten Journal: Cancer Immunol Immunother Date: 2015-04-29 Impact factor: 6.968