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August 2016

CAR-engineered natural killer cells: an adoptive cellular therapy approaching clinical application


We successfully kicked off our CellGenix Lectures with an exciting talk given by Prof. Dr. Winfried Wels about CAR-engineered NK cells. While the first CAR-T cell therapies are expected to soon obtain market approval, clinical research on CAR-engineered NK cells has only just started. The lecture was a great opportunity to learn more about this new promising adoptive cellular therapy. A lot of questions were asked and the drinks reception afterwards was thankfully used by our attendees to exchange experiences.

Abstract CellGenix Lecture
Prof. Dr. Winfried Wels, Georg-Speyer-Haus, Frankfurt, Germany
Significant progress has been made over the last decade towards realizing the potential of natural killer cells for cancer immunotherapy. In addition to donor-derived primary NK cells, also continuously expanding cytotoxic cell lines such as NK-92 are considered for adoptive cancer immunotherapy. High cytotoxicity of NK-92 has previously been shown against malignant cells of hematologic origin in preclinical studies, and general safety of infusion of NK-92 cells has been established in phase I clinical trials. To enhance their therapeutic utility, the laboratory of Winfried Wels genetically modified NK-92 cells to express chimeric antigen receptors (CARs) targeted to a variety of tumor-associated cell-surface antigens, demonstrating high and specific antitumor activity of the genetically engineered CAR NK cells against antigen-positive but otherwise NK-resistant targets. In his presentation, Winfried Wels focused in particular on a variant of NK-92 cells expressing after lentiviral transduction a second-generation CAR that consists of an ErbB2 (HER2)-specific scFv antibody fragment fused via a linker to a composite CD28-CD3ζ signaling domain. Together with partners at the Blood Donation Centers in Frankfurt and Dresden, this cell line (termed NK-92/5.28.z) is being developed as an off-the-shelf cellular therapeutic for clinical applications. Prof. Wels presented data on the functional analysis of NK-92/5.28.z cells that revealed high and stable CAR expression and selective cytotoxicity against ErbB2-expressing but otherwise NK-resistant tumor cells of different origins. Work performed together with colleagues from the Institute of Neurooncology at the University of Frankfurt currently focuses on the development of NK-92/5.28.z cells for adoptive immunotherapy of ErbB2-positive glioblastoma (GBM). In in vitro assays, NK-92/5.28.z in contrast to untargeted NK-92 cells lysed all ErbB2-positive established and primary GBM cells analyzed. Potent in vivo antitumor activity of NK-92/5.28.z was observed in orthotopic GBM xenograft models in NOD-SCID IL2Rγnull (NSG) mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area. In immunocompetent mice, local therapy with NK-92/5.28.z cells resulted in cures of transplanted syngeneic GBM in the majority of animals, induction of endogenous antitumor immunity and long-term protection against tumor rechallenge at distant sites. These data demonstrate the potential of ErbB2-specific NK-92/5.28.z cells for adoptive immunotherapy, justifying evaluation of this approach for the treatment of patients with recurrent ErbB2-positive glioblastoma. Please find more information at: www.georg-speyer-haus.de.

Since our first lecture has been so well received, we are planning to organize a second one in October.