Human natural killer cells: Advancing biology and clinical applications

摘要 在过去的几十年里，癌症的传统“护理标准”包括手术、放射治疗、放射治疗和放射治疗。 治疗，化疗和干细胞移植在一些癌症，如急性髓性白血病。在 近十年来，使用单克隆抗体如利妥昔单抗和曲妥珠单抗免疫治疗现在已经 分别纳入淋巴瘤和乳腺癌的护理标准。立即提供令人信服的数据 表明先天免疫细胞，如自然杀伤（NK）细胞是介导 抗体治疗的临床效果。我们的建议旨在加强细胞先天免疫， 增强癌症治疗。部分挑战涉及1）先天免疫系统对肿瘤细胞的有限识别 2）抑制肿瘤微环境中的先天免疫效应细胞功能;和3） 通过先天免疫效应细胞穿透肿瘤块。 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 液体和实体肿瘤的治疗。从战略上讲，这将在未来7年内实现。 1）更完整地了解人类NK细胞的发育，包括表达 激活和抑制受体; 2）优化表达嵌合NK细胞的人NK细胞的开发， 抗原受体，以及3）我们的双特异性NKG 2D抗体的完全开发， 和其他先天免疫效应细胞进入肿瘤床。我们记录的基本一致成功 沿着我们成功地翻译了一种 我们在1,000多名癌症患者中的大量临床发现都为我们提供了基础， 成功地沿着这条路沿着。在未来的七年里，我们相信我们将在以下方面引领该领域：1） 增强NK细胞肿瘤特异性; 2）增强NK细胞溶细胞效应子功能;和3）增强NK细胞肿瘤特异性; NK和其他先天免疫细胞迁移到肿瘤床中。未来7年的潜在结果 将完成一系列临床试验，首次证明在人类中具有显著的抗肿瘤活性， 最终证明携带液体或实体肿瘤的癌症患者的存活率显著延长， 表达被我们的修饰的先天免疫产物识别的抗原。

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.