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（由适用提供）：在过去的20年中，我在天然杀手（NK）细胞生物学领域持续筹集了NCI资金，免疫疗法的发展和血液学恶性肿瘤和急性髓样白血病（AML）的造血细胞移植（HCT）。我的团队开创了NK细胞的适应性转移，拥有最大的世界经验，感染了200个单倍体NK细胞产品，可以治疗血液学和实体瘤恶性肿瘤的患者。最近，我们通过鉴定由巨细胞病毒（CMV）诱导的NK细胞中的独特功能表型来描述了人类NK细胞生物学中的一种新范式。这些长寿命，高度分化的NKG2C+/CD27+细胞，我们称之为“自适应” NK细胞受过教育和富集，以表达自抑制性杀伤性杀伤性免疫球蛋白样受体（KIR）。它们代表了CMV感染小鼠中描述的类似记忆的LY49H+ NK细胞的人类等效物。此外，我们选择性地鉴定出扩展的NK细胞子集缺乏代理信号分子FCϵR1γ，EAT-2和SYK单独或组合。重要的是，它们是表观遗传学的，以增强细胞因子的产生和存活，并通过CD16介导潜在的抗体依赖性细胞毒性（ADCC）。该杰出研究者奖的总体目标是制定策略，以增强实体瘤恶性肿瘤患者内源性NK细胞的抗肿瘤活性。目的是开发“离架子”试剂以激活NK细胞，克服抑制性受体信号并将其靶向特定的肿瘤抗原。我的小组开发了几种新颖的NK细胞靶向剂，包括通过将SCFV抗CD16与SCFV融合用于肿瘤抗原的SCFV抗CD16和IL-15/IL-15Rα-FC复合物，该抗原靶向肿瘤抗原，该抗原与行业合作伙伴相关。在此提案中，我们将使用多种策略评估这些药物的治疗潜力。首先，实体瘤患者的流行病学遗传研究将定义CMV与人乳头瘤病毒（HPV）暴露之间的关系，实际上诱导的“自适应” NK细胞的发展以及癌症发展的风险以及对标准疗法的反应。其次，我们将评估一种新型实体瘤抗原Rhamm在肿瘤和“癌化”微环境中的表达。第三，我们将使用一种新型的异构模型，我们将测试使用我们独特的药物靶向RHAMM的“自适应” NK细胞的抗肿瘤效率。第四，经过临床前评估，我们将对最佳药物进行I期临床试验，以治疗销售的肿瘤恶性肿瘤，并将测试病毒疫苗在诱导或增强“自适应” NK细胞功能中的作用。最后，我将基于我的长期心态记录，将这些投资用作培训未来翻译科学家的平台。此处提出的创新研究得到了初步数据的良好支持，并代表了NK细胞生物学中令人兴奋的新兴领域。成功开发了利用先天性的“适应性” NK细胞靶向实体瘤的疗法将对癌症免疫疗法的领域产生重大影响。