NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity
Aurélie Hérault, Judy Mak, Josefa de la Cruz-Chuh, Michael Dillon, Diego Ellerman, MaryAnn Go, Ely Cosino, Robyn Clark, Emily Carson, Stacey Yeung, Mélanie Pichery, Mylène Gador, Eugene Y. Chiang, Jia Wu, Yuxin Liang, Zora Modrušan, Gautham Gampa, Jawahar Sudhamsu, Christopher C. Kemball, Victoria Cheung, Thi Thu Thao Nguyen, Dhaya Seshasayee, Robert Piskol, Klára Tótpál, Shang‐Fan Yu, Genee Lee, Katherine R. Kozak, Christoph Spiess, Kevin B. Walsh
Abstract
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.