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: 10219166
• 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/10219166
• 关键词: Acute Myelocytic Leukemia; Adoptive Transfer; Area; Award; Cell physiology; Cells; Cellular biology; Complex; Cytomegalovirus; Data; Development; Epigenetic Process; FCGR3B gene; Fc Receptor; Funding; Future; Goals; HMMR gene; Hematologic Neoplasms; Human; Human Papillomavirus; Immune; Immunoglobulins; Immunotherapy; Individual; Infection; Inflammatory; Interleukin-15; Investigation; Killer Cells; 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; bispecific killer engagers; cancer immunotherapy; cancer risk; cohort; cytokine; experience; genetic epidemiology; hematopoietic cell transplantation; industry partner; innovation; mouse model; neoplastic cell; novel; preclinical evaluation; public health relevance; receptor; response; targeted agent; therapy development; translational scientist; 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-cell 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 cancer immunotherapy.

描述（由申请人提供）：在过去的20年里，我在自然杀伤（NK）细胞生物学、免疫疗法和造血细胞移植（HCT）治疗恶性血液病和急性髓性白血病（AML）领域获得了持续的NCI资助。我的团队是NK细胞过继转移的先驱，拥有世界上最丰富的经验，已经输注了超过200种单倍体相合的NK细胞产品来治疗血液病和实体瘤恶性肿瘤患者。最近，我们描述了一个新的模式，在人类NK细胞生物学鉴定一个独特的功能表型的NK细胞诱导的巨细胞病毒（CMV）。这些长寿、高度分化的NKG 2C +/CD 27+细胞（我们称之为“适应性”NK细胞）经过训练和富集，可表达自抑制性免疫球蛋白样受体（KIR）。它们代表了CMV感染小鼠中描述的记忆样Ly 49 H + NK细胞的人类等效物。此外，我们鉴定了选择性缺乏近端信号传导分子Fc γ R1γ、EAT-2和SYK的扩增的NK细胞亚群。重要的是，它们在表观遗传学上为增强的细胞因子产生和存活做好了准备，并通过CD 16介导有效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。目标是开发“现成”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。我的团队已经开发了几种新型NK细胞靶向药物，包括通过融合抗CD 16 scFv与肿瘤抗原scFv和与行业合作伙伴开发的靶向肿瘤抗原的IL-15/IL-15 R α-Fc复合物而产生的双特异性杀伤细胞因子（BiKEs）。在本提案中，我们将使用几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学研究将确定CMV和人乳头瘤病毒（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。第二，我们将评估一种新的实体瘤抗原RHAMM，它在肿瘤和“癌变”微环境中都表达。第三，我们将使用一种新的异种模型，我们将测试用我们独特的试剂靶向RHAMM的“适应性”NK细胞的抗肿瘤功效。第四，在临床前评估之后，我们将对治疗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，我将建立在我长期的导师记录，利用这些调查作为平台，培养未来的翻译科学家。本文提出的创新研究得到了初步数据的充分支持，并代表了NK细胞生物学中令人相当兴奋的新兴领域。成功开发利用先天“适应性”NK细胞靶向实体瘤的疗法将对癌症免疫治疗领域产生重大影响。

项目成果

Natural Killer Cell-Based Immunotherapy in Gynecologic Malignancy: A Review.

• DOI: 10.3389/fimmu.2017.01825
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Uppendahl LD;Dahl CM;Miller JS;Felices M;Geller MA
• 通讯作者: Geller MA

Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1.

• DOI: 10.3390/ijms22041954
• 发表时间: 2021-02-16
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Osum SH;Watson AL;Largaespada DA
• 通讯作者: Largaespada DA

Epigenetic epidemiology as a tool to understand the role of immunity in chronic disease.

表观遗传流行病学作为了解免疫在慢性疾病中的作用的工具。

• DOI: 10.2217/epi-2016-0055
• 发表时间: 2016
• 期刊: Epigenomics
• 影响因子: 3.8
• 作者: Nelson,HeatherH;Kelsey,KarlT
• 通讯作者: Kelsey,KarlT

Cytomegalovirus infection in malignant pleural mesothelioma.

• DOI: 10.1371/journal.pone.0254136
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hunter-Schlichting D;Kelsey KT;Demmer R;Patel M;Bueno R;Christensen B;Fujioka N;Kolarseri D;Nelson HH
• 通讯作者: Nelson HH

Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer.

• DOI: 10.1038/s41698-022-00323-2
• 发表时间: 2022-11-02
• 期刊: NPJ PRECISION ONCOLOGY
• 影响因子: 7.9
• 作者: Shi, Xiaolei;Day, Abderrahman;Bergom, Hannah E.;Tape, Sydney;Baca, Sylvan C.;Sychev, Zoi E.;Larson, Gabrianne;Bozicevich, Asha;Drake, Justin M.;Zorko, Nicholas;Wang, Jinhua;Ryan, Charles J.;Antonarakis, Emmanuel S.;Hwang, Justin
• 通讯作者: Hwang, Justin