8th Annual Symposium
Physics of Cancer
Leipzig, Germany
October 4-6, 2017
Invited Talk
From “CAR T cells” to CAR expressing NK cells for cancer retargeting
Ulrike Köhl1, Olaf Oberschmidt1, Michael Morgan2, Michael Heuser3, Julia Suerth2, Julia Dahlke2, Ruth Esser1, Wolfgang Glienke1, Krasimira Aleksandrova1, Christoph Priesner1, Jana Leise1, Lubomir Arseniev1, Axel Schambach2, Stephan Kloess1
1Institute of Cellular Therapeutics, Hannover Medical School (MHH), Hannover, Germany
2Institute of Experimental Hematology, MHH, Hannover, Germany
3Hematology, Hemostasis, Oncology and Stem Cell Transplantation, MHH, Hannover, Germany
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A short summary of clinical studies using chimeric antigen receptor (CAR)-modified T cells for the treatment of malignancies will be presented, which is an increasing field leading to promising results with improved survival in patients with leukemia. Recently, we optimized a fully closed and automated system for the manufacturing of autologous CAR T cells in order to treat patients with Melanoma in a phase I trial.

In contrast to T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease, which makes them a promising source for third-party-donor immunotherapy. However, tumor cells can escape NK cell cytotoxicity by tumor immune escape mechanisms (TIEMs). In order to overcome TIEMs and to make NK cell-based therapies more specific, we engineered primary human NK cells to express a CAR designed to recognize CD19 or CD123, which is highly expressed on the surface of primary acute lymphoblastic or myeloid leukemia, respectively. NK cells were transduced with state-of-the-art alpharetroviral self-inactivating (SIN) vectors encoding EGFP alone as control or a third generation CAR engineered with an anti-CD19 or anti-CD123 single chain variable fragment (scFv) and containing the CD28 transmembrane domain, the 4-1BB costimulatory domain, the CD3ζ signaling domain and an internal ribosomal entry site (IRES) element for EGFP expression. CAR-modified NK cells showed a strongly improved cytotoxicity against leukemic cells compared to activated NK cells with a nearly complete elimination of leukemic cells after 48 h. Finally, this will be reviewed in the context of mainly pre-clinical data published on retargeting NK cells, with an outline of possible advantages using these short-lived donor effector cells as an “off the shelf product”.
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