Herault et al. demonstrated the efficacy of targeting the costimulatory receptor NKG2D with a bispecific antibody (BsAb) to enhance NK- and CD8+ T cell-mediated antitumor immunity. NKG2D was expressed on intratumoral CD8+ T cells and was associated with better prognosis in atezolizumab-treated TNBC patients. An NKG2D BsAb that bound to NKG2D on NK or CD8+ T cells and HER2 on breast cancer cells (HER2-CRB) formed immunological synapses on NK cells, enhancing NK cell activation and cytokine production. In murine models, mouse surrogate HER2-CRB with a T cell-dependent BsAb enhanced T cell cytotoxicity, cytokine production, and antitumor efficacy.
Contributed by Shishir Pant
BACKGROUND: Cancer immunotherapy approaches that elicit immune cell responses, including T and NK cells, have revolutionized the field of oncology. However, immunosuppressive mechanisms restrain immune cell activation within solid tumors so additional strategies to augment activity are required. METHODS: We identified the co-stimulatory receptor NKG2D as a target based on its expression on a large proportion of CD8+ tumor infiltrating lymphocytes (TILs) from breast cancer patient samples. Human and murine surrogate NKG2D co-stimulatory receptor-bispecifics (CRB) that bind NKG2D on NK and CD8+ T cells as well as HER2 on breast cancer cells (HER2-CRB) were developed as a proof of concept for targeting this signaling axis in vitro and in vivo. RESULTS: HER2-CRB enhanced NK cell activation and cytokine production when co-cultured with HER2 expressing breast cancer cell lines. HER2-CRB when combined with a T cell-dependent-bispecific (TDB) antibody that synthetically activates T cells by crosslinking CD3 to HER2 (HER2-TDB), enhanced T cell cytotoxicity, cytokine production and in vivo antitumor activity. A mouse surrogate HER2-CRB (mHER2-CRB) improved in vivo efficacy of HER2-TDB and augmented NK as well as T cell activation, cytokine production and effector CD8+ T cell differentiation. CONCLUSION: We demonstrate that targeting NKG2D with bispecific antibodies (BsAbs) is an effective approach to augment NK and CD8+ T cell antitumor immune responses. Given the large number of ongoing clinical trials leveraging NK and T cells for cancer immunotherapy, NKG2D-bispecifics have broad combinatorial potential.
Author Info: (1) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (2) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (3) Department of Bioc
Author Info: (1) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (2) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (3) Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA. (4) Department of Antibody Engineering, Genentech, South San Francisco, CA, USA. (5) Department of Antibody Engineering, Genentech, South San Francisco, CA, USA. (6) Department of In Vivo Pharmacology, Genentech, South San Francisco, CA, USA. (7) Department of In Vivo Pharmacology, Genentech, South San Francisco, CA, USA. (8) Department of In Vivo Pharmacology, Genentech, South San Francisco, CA, USA. (9) Department of In Vivo Pharmacology, Genentech, South San Francisco, CA, USA. (10) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (11) Immuno-Oncology-In Vitro Biology Department, Evotec, Toulouse, France. (12) Immuno-Oncology-In Vitro Biology Department, Evotec, Toulouse, France. (13) Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. (14) Department of Antibody Discovery, Genentech, South San Francisco, CA, USA. (15) Department of Next-GenSequencing, South San Francisco, CA, USA. (16) Department of Next-GenSequencing, South San Francisco, CA, USA. (17) Department of Development Sciences PTPK, Genentech, South San Francisco, CA, USA. (18) Department of Structural Biology, Genentech, South San Francisco, CA, USA. (19) Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA. (20) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (21) Department of Bioinformatics, Genentech, South San Francisco, CA, USA. (22) Department of Antibody Discovery, Genentech, South San Francisco, CA, USA. (23) Department of Bioinformatics, Genentech, South San Francisco, CA, USA. (24) Department of In Vivo Pharmacology, Genentech, South San Francisco, CA, USA. (25) Department of In Vivo Pharmacology, Genentech, South San Francisco, CA, USA. (26) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (27) Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA. (28) Department of Antibody Engineering, Genentech, South San Francisco, CA, USA. (29) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. walshk6@gene.com.
