8th Annual Symposium
Physics of Cancer
October 4-6, 2017
|PoC - Physics of Cancer - Annual Symposium|
From “CAR T cells” to CAR expressing NK cells for cancer retargeting
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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”.