Peipp et al. used immunoligands consisting of a CD20 single-chain variable fragment linked to an NKG2D ligand (either MICA or ULBP2) to increase the surface density of NKG2D ligand on CD20+ lymphoma cell lines and CLL cells from patients. This engaged γδ T cells in target killing in a dose-dependent manner, and a combination with the γδ TCR agonist BrHPP further enhanced the efficacy in vitro.
Human gammadelta T cells are innate-like T cells which are able to kill a broad range of tumor cells and thus may have potential for cancer immunotherapy. The activating receptor natural killer group 2 member D (NKG2D) plays a key role in regulating immune responses driven by gammadelta T cells. Here, we explored whether recombinant immunoligands consisting of a CD20 single-chain fragment variable (scFv) linked to a NKG2D ligand, either MHC class I chain-related protein A (MICA) or UL16 binding protein 2 (ULBP2), could be employed to engage gammadelta T cells for tumor cell killing. The two immunoligands, designated MICA:7D8 and ULBP2:7D8, respectively, enhanced cytotoxicity of ex vivo expanded gammadelta T cells against CD20-positive lymphoma cells. Both Vdelta1 and Vdelta2 gammadelta T cells were triggered by MICA:7D8 or ULBP2:7D8. Killing of CD20-negative tumor cells was not induced by the immunoligands, indicating their antigen-specificity. MICA:7D8 and ULBP2:7D8 acted in a dose-dependent manner and induced cytotoxicity at nanomolar concentrations. Importantly, chronic lymphocytic leukemia (CLL) cells isolated from patients were sensitized by the two immunoligands for gammadelta T cell-cytotoxicity. In a combination approach the immunoligands were combined with bromohydrin pyrophosphate (BrHPP), an agonist for Vdelta2 gammadelta T cells, which further enhanced the efficacy in target cell killing. Thus, employing tumor-directed recombinant immunoligands which engage NKG2D may represent an attractive strategy to enhance anti-tumor cytotoxicity of gammadelta T cells. This article is protected by copyright. All rights reserved.
Author Info: (1) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. (2) Institute of Immunology, Christi
Author Info: (1) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. (2) Institute of Immunology, Christian-Albrechts-University of Kiel, Kiel, Germany. (3) Institute of Immunology, Christian-Albrechts-University of Kiel, Kiel, Germany. (4) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. (5) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. (6) Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. Genmab, Utrecht, The Netherlands. (7) Genmab, Utrecht, The Netherlands. Dept. of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. (8) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. (9) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. (10) Institute of Immunology, Christian-Albrechts-University of Kiel, Kiel, Germany. (11) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. (12) Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
