Article
作者: Seshasayee, Dhaya ; Spiess, Christoph ; Clark, Robyn ; Nguyen, Thi Thu Thao ; Liang, Yuxin ; de la Cruz-Chuh, Josefa ; Wu, Jia ; Kemball, Christopher C ; Sudhamsu, Jawahar ; Walsh, Kevin B ; Yeung, Stacey ; Gampa, Gautham ; Carson, Emily ; Modrusan, Zora ; Totpal, Klara ; Ellerman, Diego ; Lee, Genee ; Cosino, Ely ; Kozak, Katherine R ; Go, MaryAnn ; Yu, Shang-Fan ; Pichery, Melanie ; Chiang, Eugene Y ; Herault, Aurelie ; Mak, Judy ; Cheung, Victoria ; Dillon, Michael A ; Gador, Mylène ; Piskol, Robert
BACKGROUNDCancer 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.METHODSWe 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.RESULTSHER2-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.CONCLUSIONWe 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.
