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