Adaptive NK Cell Therapy to Improve UCB Transplant Outcomes

适应性 NK 细胞疗法可改善 UCB 移植结果

• 批准号: 8931153
• 负责人: Jeffrey S. Miller
• 金额: $ 30.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8931153
• 关键词: Activated Natural Killer Cell; Acute Myelocytic Leukemia; Address; Adoption; Allogenic; Antigen Targeting; Antigens; Autologous; Biology; Blood; Blood Component Removal; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Data; Clinical Trials; Complex; Cytomegalovirus; Data; Disease remission; Education; Effector Cell; Exhibits; FCGR3B gene; Fc Receptor; Funding; Goals; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hour; Human; Immune; Immunologic Memory; Individual; Infection; Inflammatory; Infusion procedures; Interleukin-12; Interleukin-15; Interleukin-18; Ligation; Lymphocyte; MHC Class I Genes; Malignant Neoplasms; Mediating; Memory; Methods; Modeling; Modification; Mus; NK Cell Activation; Names; Natural Killer Cells; Outcome; Pathway interactions; Patients; Phenotype; Population; Production; Property; Publications; Refractory; Relapse; Research; Resolution; Risk; Role; SYK gene; Safety; Sampling; Signal Transduction; Signaling Molecule; Specificity; T-Lymphocyte; Testing; Therapeutic; Therapeutic antibodies; Translating; Transplant Recipients; Transplantation; Treatment Failure; Tumor Antigens; Umbilical Cord Blood Transplantation; abstracting; antibody-dependent cell cytotoxicity; base; biobank; conditioning; cytokine; design; disorder later incidence prevention; hematopoietic cell transplantation; high risk; human FRAP1 protein; improved; in vitro activity; in vivo; interleukin-15 receptor; killings; neoplastic cell; novel; pre-clinical; prevent; primary outcome; public health relevance; reconstitution; research clinical testing; response; seropositive; success; tumor

Abstract/Project Summary: Natural killer (NK) cells are important immune cells that protect the host from infection and cancer. They are homeostatically regulated by IL-15 trans-presented in the context of IL-15R. We have established the anti-leukemic effect of allogeneic NK cell infusions, but host rejection of adoptively transferred NK cells and lack of NK cell specificity to tumor antigens limit their treatment success. During the current funding period we developed novel agents to target NK cells to tumors. These include bi-specific killer engagers (BiKEs), scFv anti-CD16 fusions with anti-CD33 or anti-PR1, and 15/IL-15R-Fc complexes targeted to CD33. The goal of this proposal is to address relapse after non-myeloablative umbilical cord blood transplantation (UCBT), which is the major cause of treatment failure with relapse rates of 35%. Our data demonstrate that after UCBT NK cells are abundant but dysfunctional. However, individuals who activate cytomegalovirus (CMV) develop highly differentiated NKG2C+ NK cells. These cells, which we have named adaptive NK cells have an educated phenotype, are enriched for the expression of self-inhibitory KIRs and represent the human equivalent of the memory NK cells described in CMV-infected mice. Publications from our group established that after UCBT these adaptive NK cells have heightened effector functions that persist for at least one year. Our extensive preliminary data show that NKG2C is not the only marker for CMV-induced adaptive NK cells. We identified expansions of NK cells selectively lacking the proximal signaling molecules FcεR1γ, EAT-2 and SYK individually or in combination in UCBT recipients who reactivated CMV. Adaptive NK cells are epigenetically primed for enhanced cytokine production, survival, and increased expression of mTOR pathway adaptors. Further, they are functionally specialized for antibody-dependent cellular cytotoxicity (ADCC) through CD16. We will translate this research to develop minimally manipulative methods to activate NK cells and prolong their survival such as overnight ex vivo incubation with IL-15, IL-12 and IL-18. . We have also developed strategies to make NK cells antigen specific with the use of “off-the-shelf” activation/targeting strategies. Our OVERARCHING HYPOTHESIS is that adaptive NK cells can be activated and targeted to induce antigen-specific killing to prevent or treat relapse after UCBT. In SA1, we will evaluate the clinical impact of IL-15 signaling on adaptive NK cells by analyzing samples from our biorepository with mature clinical data. We will also perform clinical trials in patients with hematologic malignancies undergoing non- myeloablative UCBT. The primary objective of these trials is to safely induce expansion of activated adaptive NK cells. In SA2, activation and antigen targeting of NK cells will be studied for prevention of relapse using an AML xenogeneic model to pick the best strategy to move into clinical testing in year 3. These targeted approaches include 1) IL-15/IL-15R-Fc and anti-CD16x33 BiKE; 2) IL-15/IL-15R-Fc-anti-CD33 complexes; or 3) IL-15/IL-15R-Fc and anti-CD16xPR1 BiKE.

摘要/项目摘要：自然杀手（NK）细胞是保护宿主免受的重要免疫细胞 感染和癌症。它们在IL-15R的背景下由IL-15跨表现的IL-15调节。 我们已经建立了同种异体NK细胞输注的抗白血病效应，但宿主拒绝适当 转移的NK细胞和缺乏NK细胞对肿瘤抗原的特异性限制了其治疗成功。在 当前的资金期我们开发了新颖的药物将NK细胞靶向肿瘤。这些包括双重杀手 探空剂（自行车），抗CD16抗CD33或抗PR1的抗CD16融合，以及15/IL-15R-FC复合物的目标 到CD33。该提议的目的是解决非毛刺脐带血后的缓解 移植（UCBT），这是造成治疗失败的主要原因，退休率为35％。我们的数据 证明在UCBT NK细胞后丰富但功能失调。但是，激活的个人 巨细胞病毒（CMV）会形成高度分化的NKG2C+ NK细胞。这些细胞，我们已经命名 自适应NK细胞具有受过良好教育的表型，以表达自抑制性KIR和 表示在CMV感染的小鼠中描述的记忆NK细胞的人类当量。我们的出版物 小组确定，在UCBT之后，这些自适应NK细胞具有增强的效应子功能，持续存在 至少一年。我们广泛的初步数据表明，NKG2C并不是CMV诱导的唯一标记 自适应NK细胞。我们确定了NK细胞的膨胀，选择性缺乏代理信号分子 FCεR1γ，EAT-2和SYK单独或在重新激活CMV的UCBT受体中组合。自适应nk 细胞表观遗传启动，以增强细胞因子的产生，存活和MTOR的表达增加 路径适配器。此外，它们在功能上专门用于抗体依赖性细胞毒性 （ADCC）通过CD16。我们将翻译这项研究以开发最小操纵的方法以激活 NK细胞并延长其生存率，例如与IL-15，IL-12和IL-18的过夜生存孵育。 。我们有 还制定了通过使用“现成”激活/靶向来使NK细胞抗原特定的抗原抗原的策略 策略。我们的总体假设是自适应NK细胞可以被激活并针对 诱导特定于抗原特异性杀戮，以防止或治疗UCBT后的救济。在SA1中，我们将评估临床 IL-15信号传导对自适应NK细胞的影响通过我们的生物验证的分析样品具有成熟的临床 数据。我们还将在患有非 - 骨髓性UCBT。这些试验的主要目的是安全诱导活化自适应的扩展 NK细胞。在SA2中，将研究NK细胞的激活和抗原靶向使用 AML异类模型以选择第3年进行临床测试的最佳策略。 方法包括1）IL-15/IL-15R-FC和抗CD16X33自行车； 2）IL-15/IL-15R-FC-ANTI-CD33复合物； 或3）IL-15/IL-15R-FC和抗CD16XPR1自行车。