Viral priming and targeting NK cells against solid tumor malignancies

病毒启动和靶向 NK 细胞对抗实体瘤恶性肿瘤

• 批准号: 8952308
• 负责人: Jeffrey S. Miller
• 金额: $ 91.2万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952308
• 关键词: Activated Natural Killer Cell; Acute Myelocytic Leukemia; Adoptive Transfer; Area; Award; Cell physiology; Cells; Cellular biology; Complex; Cytomegalovirus; Data; Development; FCGR3B gene; Fc Receptor; Funding; Future; Goals; HMMR gene; Health; Hematologic Neoplasms; Human; Human Papillomavirus; Immune; Immunoglobulins; Immunotherapy; Infection; Inflammatory; Interleukin-15; Investigation; Life; Malignant Neoplasms; Mediating; Memory; Mentors; Mentorship; Modeling; Mus; Names; Natural Killer Cells; Patients; Phase I Clinical Trials; Phenotype; Population; Production; Reagent; Receptor Signaling; Reporting; Research; Research Personnel; Risk; Role; SYK gene; Sampling Studies; Scientist; Signaling Molecule; Solid Neoplasm; Testing; Therapeutic; Therapeutic antibodies; Training; Translational Research; Tumor Antigens; Viral; Viral Vaccines; antibody-dependent cell cytotoxicity; cancer risk; cohort; cytokine; experience; genetic epidemiology; hematopoietic cell transplantation; industry partner; innovation; killings; mouse model; neoplastic cell; novel; preclinical evaluation; receptor; response; therapy development; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): During the last 2 decades I have had continuous NCI-funding in the areas of natural killer (NK) cell biology, development of immunotherapies and hematopoietic cell transplantation (HCT) for hematologic malignancies and acute myeloid leukemia (AML). My team, who pioneered adoptive transfer of NK cells, has the largest world experience having infused >200 haploidentical NK cell products to treat patients with hematologic and solid tumor malignancies. Recently we described a new paradigm in human NK cell biology by identifying a unique functional phenotype in NK cells induced by cytomegalovirus (CMV). These long-lived, highly differentiated NKG2C+/CD27+ cells, which we call "adaptive" NK cells are educated and enriched for the expression of self-inhibitory killer-cel immunoglobulin-like receptors (KIR). They represent the human equivalent of the memory-like Ly49H+ NK cells described in CMV-infected mice. Further, we identified expanded NK cell subsets selectively lacking the proximal signaling molecules FcϵR1γ, EAT-2 and SYK individually or in combination. Importantly, they are epigenetically primed for enhanced cytokine production and survival, and mediate potent antibody-dependent cellular cytotoxicity (ADCC) through CD16. The overarching goal of this Outstanding Investigator Award is to develop strategies to enhance the anti-tumor activity of endogenous NK cells in patients with solid tumor malignancies. The objective is to develop "off the shelf" reagents to activate NK cells, overcome inhibitory receptor signaling, and target them to specific tumor antigens. My group has developed several novel NK cell targeting agents, including bi-specific killer engagers (BiKEs), created by fusing scFv anti-CD16 with scFv for tumor antigens and IL-15/IL-15Rα-Fc complexes targeted to tumor antigens developed with an industry partner. In this proposal, we will evaluate the therapeutic potential for these agents using several strategies. First, epidemiologic genetic studies in patients with solid tumors will define the relationship between CMV and human papillomavirus (HPV) exposure, the development of virally-induced "adaptive" NK cells and the risk of cancer development and response to standard therapies. Second, we will evaluate a novel solid tumor antigen, RHAMM, expressed both on tumors and in the "cancerized" microenvironment. Third, we will use a novel xenogeneic model we will test the anti-tumor efficacy of "adaptive" NK cells targeted to RHAMM with our unique agents. Fourth, after preclinical evaluations, we will conduct phase I clinical trials of the optimal agents to treat sold tumor malignancies and will test the role of viral vaccines in inducing or enhancing "adaptive" NK cell function. Lastly, I will build on my long track record of mentorship to use these investigations as a platform to train future translational scientists. The innovative studies proposed here are well supported by preliminary data and represent an emerging area of considerable excitement in NK cell biology. The successful development of therapies to harness innate "adaptive" NK cells to target solid tumors will have a substantial impact the field of cance immunotherapy.

简介(申请人提供)：在过去的20年里，我一直在自然杀伤(NK)细胞生物学、免疫疗法的开发以及血液系统恶性肿瘤和急性髓系白血病(AML)的造血细胞移植(HCT)领域获得NCI资助。我的团队是NK细胞采用移植的先驱，拥有世界上最大的经验，曾输注&gt；200种半相合的NK细胞产品来治疗血液系统和实体肿瘤恶性肿瘤患者。最近，我们通过鉴定巨细胞病毒(CMV)诱导的NK细胞中一种独特的功能表型，描述了一种新的人类NK细胞生物学范式。这些长寿的、高度分化的NKG2C+/CD27+细胞，我们称之为“适应性”NK细胞，培养和丰富了自我抑制性杀伤细胞免疫球蛋白样受体(KIR)的表达。它们相当于人类在感染CMV的小鼠中描述的记忆样Ly49H+NK细胞。此外，我们鉴定了扩增的NK细胞亚群选择性地缺乏近端信号分子FcϵR1γ、EAT-2和SYK单独或联合使用。重要的是，它们在表观遗传学上为增强细胞因子的产生和存活做好了准备，并通过CD16介导了强大的抗体依赖的细胞毒性(ADCC)。这一杰出研究人员奖的首要目标是开发策略，以增强实体瘤恶性肿瘤患者内源性NK细胞的抗肿瘤活性。其目的是开发现成的试剂来激活NK细胞，克服抑制受体信号，并将它们靶向于特定的肿瘤抗原。我的团队已经开发了几种新型的NK细胞靶向药物，包括通过融合抗CD16单链抗体和肿瘤抗原单链抗体而创建的双特异性杀伤分子(BIKES)，以及与行业合作伙伴开发的靶向肿瘤抗原的IL-15/IL-15Rα-Fc复合体。在这项提案中，我们将使用几种策略来评估这些药物的治疗潜力。首先，实体肿瘤患者的流行病学遗传学研究将确定巨细胞病毒与人类乳头瘤病毒(HPV)暴露之间的关系，病毒诱导的“适应性”NK细胞的发展，以及癌症发展的风险和对标准治疗的反应。其次，我们将评估一种新的固体肿瘤抗原RHAMM，它既表达在肿瘤上，也表达在“癌变”的微环境中。第三，我们将使用一种新的异种模型，我们将测试我们独特的药物靶向rhamm的“适应性”NK细胞的抗肿瘤效果。第四，在临床前评估后，我们将对治疗已售出的肿瘤恶性肿瘤的最佳药物进行I期临床试验，并将测试病毒疫苗在诱导或增强“适应性”NK细胞功能方面的作用。最后，我将在我长期指导的基础上，利用这些研究作为培训未来翻译科学家的平台。这里提出的创新研究得到了初步数据的很好支持，并代表了NK细胞生物学中一个令人相当兴奋的新兴领域。利用天然的“适应性”NK细胞靶向实体肿瘤的治疗方法的成功开发，将对肿瘤免疫治疗领域产生重大影响。