Aurelie Herault, Judy Mak, Josefa de la Cruz-Chuh, Michael A Dillon, Diego Ellerman, MaryAnn Go, Ely Cosino, Robyn Clark, Emily Carson, Stacey Yeung, Melanie Pichery, Mylène Gador, Eugene Y Chiang, Jia Wu, Yuxin Liang, Zora Modrusan, Gautham Gampa, Jawahar Sudhamsu, Christopher C Kemball, Victoria Cheung, Thi Thu Thao Nguyen, Dhaya Seshasayee, Robert Piskol, Klara Totpal, Shang-Fan Yu, Genee Lee, Katherine R Kozak, Christoph Spiess, Kevin B Walsh
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However, immunosuppressive mechanisms restrain immune cell activation within solid tumors so additional strategies to augment activity are required.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>We demonstrate that targeting NKG2D with bispecific antibodies (BsAbs) is an effective approach to augment NK and CD8+ T cell antitumor immune responses. 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引用次数: 0
摘要
背景:激发免疫细胞(包括 T 细胞和 NK 细胞)反应的癌症免疫疗法为肿瘤学领域带来了革命性的变化。然而,免疫抑制机制抑制了实体瘤内免疫细胞的活化,因此需要更多增强活性的策略:方法:根据乳腺癌患者样本中大量 CD8+ 肿瘤浸润淋巴细胞(TILs)上 NKG2D 的表达,我们确定了共刺激受体 NKG2D 作为靶点。作为体外和体内靶向这一信号轴的概念验证,我们开发了与 NK 和 CD8+ T 细胞上的 NKG2D 以及乳腺癌细胞上的 HER2 结合的人类和小鼠代用 NKG2D 协同刺激受体双特异性药物(CRB):结果:与表达 HER2 的乳腺癌细胞系共同培养时,HER2-CRB 可增强 NK 细胞的活化和细胞因子的产生。HER2-CRB与T细胞依赖性双特异性(TDB)抗体(通过将CD3与HER2交联合成激活T细胞的抗体)结合,可增强T细胞的细胞毒性、细胞因子生成和体内抗肿瘤活性。小鼠代用 HER2-CRB(mHER2-CRB)提高了 HER2-TDB 的体内疗效,并增强了 NK 以及 T 细胞的活化、细胞因子的产生和效应 CD8+ T 细胞的分化:我们证明了用双特异性抗体(BsAbs)靶向 NKG2D 是增强 NK 和 CD8+ T 细胞抗肿瘤免疫反应的有效方法。鉴于目前正在进行大量利用 NK 和 T 细胞进行癌症免疫治疗的临床试验,NKG2D 双特异性抗体具有广泛的组合潜力。
NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity.
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.
期刊介绍:
Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions.
The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.