Human natural killer cells: Advancing biology and clinical applications

摘要 在过去的几十年里，癌症的传统“标准护理”包括手术、放射治疗 一些癌症的治疗、化疗和干细胞移植，如急性髓系白血病。在 在过去的十年里，使用诸如利妥昔单抗和曲祖单抗等单抗的免疫疗法现在已经 分别纳入了淋巴瘤和乳腺癌的护理标准。当前令人信服的数据 表明先天免疫细胞，如自然杀伤(NK)细胞是介导 抗体治疗的临床疗效。我们的建议旨在加强细胞先天免疫，以 加强癌症治疗。挑战的一部分与1)先天免疫对肿瘤细胞的有限识别有关 效应细胞；2)肿瘤微环境中天然免疫效应细胞功能的抑制；以及3) 先天免疫效应细胞对肿瘤块的穿透。 我们的愿景是将激活的、肿瘤抗原特异性的先天免疫效应细胞疗法添加到现有的 抗液体和固体肿瘤的武器。从战略上讲，这将在未来7年内完成 多年来：1)更全面地了解人类NK细胞的发育，包括表达 2)优化表达嵌合基因的人NK细胞的发育 抗原受体，以及3)我们的双特异性NKG2D抗体的充分发展，将带来人类NK细胞 和其他先天免疫效应细胞进入肿瘤床。我们记录的基本服务持续取得成功 几十年来对NK细胞发育和效应器功能的研究，以及我们成功翻译的 我们在超过1,000名癌症患者的临床上的大量发现都是我们 成功地沿着这条道路前进。在接下来的七年里，我们相信我们将在以下方面引领行业：1) 增强NK细胞肿瘤特异性；2)增强NK细胞杀伤效应功能；3)增强 NK和其他先天免疫细胞向肿瘤床迁移。未来7年的潜在结果 将完成一系列临床试验，首次证明人类和 最终证明携带液体或固体肿瘤的癌症患者的生存期显著延长 表达的抗原将被我们改良的天然免疫产品识别。

ABSTRACT The traditional “standard of care” for cancer over the past several decades has consisted of surgery, radiation therapy, chemotherapy, and stem cell transplantation in some cancers such as acute myeloid leukemia. In the last decade, immune therapy using monoclonal antibodies such as rituximab and traztuzumab have now been incorporated into the standard of care for lymphoma and breast cancer, respectively. Compelling data now shows that that innate immune cells, such as natural killer (NK) cells are an important component mediating the clinical effectiveness of antibody therapy. Our proposal aims to strengthen cellular innate immunity to enhance cancer therapy. Part of the challenge relates to 1) limited recognition of tumor cells by innate immune effector cells; 2) dampening of innate immune effector cell function in the tumor microenvironment; and 3) penetration of the tumor mass by innate immune effector cells. Our vision is to add activated, tumor antigen specific innate immune effector cell therapy to the existing armamentarium against both liquid and solid tumors. Strategically, this will be accomplished over the next 7 years through: 1) a more complete understanding human NK cell development, including the expression of activating and inhibitory receptors; 2) optimizing the development of human NK cells expressing chimeric antigen receptors, and 3) full development of our bi-specific NKG2D antibody that will bring human NK cells and other innate immune effector cells into the tumor bed. Our documented consistent success with basic research on NK cell development and effector function over decades, along with our successful translation of a multitude of our discoveries to the clinic in over 1,000 cancer patients both serve as a foundation for us to successfully proceed along this pathway. In the next seven years, we believe we will lead the field in: 1) enhancing NK cell tumor specificity; 2) enhancing NK cell cytolytic effector function; and 3) enhancing migration of NK and other innate immune cells into the tumor bed. The potential outcome over the next 7 years will be the completion of a series of clinical trials that first demonstrate significant anti-tumor activity in man and ultimately demonstrate significantly prolonged survival of cancer patients bearing liquid or solid tumors that express antigens to be recognized by our modified innate immune products.