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.

描述（由申请人提供）：在过去 20 年中，我在自然杀伤 (NK) 细胞生物学、针对血液恶性肿瘤和急性髓性白血病 (AML) 的免疫疗法开发和造血细胞移植 (HCT) 领域持续获得 NCI 资助我的团队是 NK 细胞过继转移的先驱，拥有输注超过 200 种半相合 NK 细胞产品来治疗患者的丰富经验。最近，我们通过鉴定巨细胞病毒 (CMV) 诱导的 NK 细胞的独特功能表型，描述了人类 NK 细胞生物学的新范例，我们将其称为“适应性”。 NK 细胞经过训练和富集，可以表达自我抑制性杀伤细胞免疫球蛋白样受体 (KIR)。它们代表了人类的记忆样受体此外，我们还鉴定了感染 CMV 的小鼠中选择性缺乏近端信号分子 FcϵR1γ、EAT-2 和 SYK 的 NK 细胞亚群，重要的是，它们在表观遗传学上增强了细胞因子的产生和存活。通过 CD16 介导有效的抗体依赖性细胞毒性 (ADCC) 该杰出研究者奖的首要目标是制定增强抗肿瘤活性的策略。我们的目标是开发“现成的”试剂来激活 NK 细胞，克服抑制性受体信号传导，并将其靶向特定的肿瘤抗原。 ，包括双特异性杀伤接合剂 (BiKE)，通过将 scFv 抗 CD16 与肿瘤抗原的 scFv 融合而创建，以及针对肿瘤抗原开发的 IL-15/IL-15Rα-Fc 复合物在这项提案中，我们将使用多种策略评估这些药物的治疗潜力，首先，对实体瘤患者进行流行病学遗传学研究，以确定 CMV 与人乳头瘤病毒 (HPV) 暴露、病毒感染发展之间的关系。其次，我们将评估在肿瘤和“癌化”微环境中表达的新型实体瘤抗原 RHAMM。第四，在临床前评估后，我们将针对治疗肿瘤恶性肿瘤的最佳药物进行 I 期临床试验，并测试 RHAMM 的异种模型。最后，我将在我长期的指导记录的基础上，利用这些研究作为培训未来转化科学家的平台。利用先天“适应性”NK 细胞靶向实体瘤的疗法的成功开发将对癌症免疫治疗领域产生重大影响。