Targeted NK cells display potent activity against glioblastoma and induce protective antitumor immunity
Congcong Zhang1,3, Michael C. Burger2,3, Anja Waldmann1, Torsten Tonn4, Joachim P. Steinbach2,3, Winfried S. Wels1,3
1Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany
2Institute for Neurooncology, Goethe University, Frankfurt, Germany; 3German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, Germany; 4Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, Dresden, Germany
Significant progress has been made over the last decade towards realizing the potential of natural killer (NK) cells for cancer immunotherapy. In addition to donor-derived primary NK cells, also the cytotoxic cell line NK-92 is being considered for adoptive cancer immunotherapy. To enhance their therapeutic utility, here we genetically modified NK-92 cells to express an ErbB2-specific chimeric antigen receptor (CAR) with a composite CD28-CD3 zeta signaling domain. GMP-compliant protocols for vector production, lentiviral transduction and expansion of a CAR NK-92 single cell clone (NK-92/5.28.z) were established. Ongoing work focuses on the development of these cells for adoptive immunotherapy of glioblastoma (GBM). We evaluated the activity of NK-92/5.28.z cells against a panel of GBM cell lines and primary cultures and demonstrated selective in vitro cell killing that was dependent on ErbB2 expression by the target cells. Potent in vivo antitumor activity of NK-92/5.28.z was observed in orthotopic GBM xenograft models in NSG mice. In immunocompetent mice, local therapy with NK-92/5.28.z cells resulted in cures of transplanted syngeneic GBM in the majority of mice, induction of endogenous antitumor immunity and long-term protection against tumor rechallenge at distant sites. Our results suggest adoptive transfer of NK-92/5.28.z cells as a promising new immunotherapy approach for GBM. Preparation for a phase I clinical trial investigating NK-92/5.28.z cells as a treatment for recurrent ErbB2-positive GBM is ongoing.
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