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: 9769658
• 负责人: Jeffrey S. Miller
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769658
• 关键词: Acute Myelocytic Leukemia; Address; Adoption; Adoptive Transfer; Allogenic; Antigen Targeting; Antigens; Autologous; Biology; Blood; Blood Component Removal; Cell Differentiation process; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Data; Clinical Trials; Complex; Cytomegalovirus; Data; Disease remission; Education; Effector Cell; Epigenetic Process; Exhibits; FCGR3B gene; FRAP1 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; Role; SYK gene; Safety; Sampling; Signal Transduction; Signaling Molecule; Specificity; T-Lymphocyte; Testing; Therapeutic; Therapeutic antibodies; Translating; Transplant Recipients; Treatment Failure; Tumor Antigens; Umbilical Cord Blood Transplantation; antibody-dependent cell cytotoxicity; base; biobank; bispecific killer engagers; conditioning; curative treatments; cytokine; design; disorder later incidence prevention; first-in-human; hematopoietic cell transplantation; high risk; improved; in vitro activity; in vivo; interleukin-15 receptor; neoplastic cell; novel; pre-clinical; prevent; primary outcome; public health relevance; reconstitution; relapse risk; 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：自然杀伤 (NK) 细胞是重要的免疫细胞，可保护宿主免受 它们受 IL-15Rα 背景下反式呈递的 IL-15 的稳态调节。 我们已经确定了同种异体 NK 细胞输注的抗白血病作用，但宿主对过继性排斥 转移的 NK 细胞和缺乏对肿瘤抗原的 NK 细胞特异性限制了其治疗的成功。 目前的资助期间，我们开发了针对肿瘤的 NK 细胞的新型药物。 接合器 (BiKE)、scFv 抗 CD16 与抗 CD33 或抗 PR1 融合以及靶向 15/IL-15Rα-Fc 复合物 该提案的目标是解决非清髓性脐带血后的复发问题。 移植 (UCBT)，这是治疗失败的主要原因，我们的数据显示复发率为 35%。 证明 UCBT 后 NK 细胞数量丰富但功能失调，但激活的个体。 巨细胞病毒 (CMV) 会发育出高度分化的 NKG2C+ NK 细胞，我们将其命名为 NK 细胞。 适应性 NK 细胞具有受过教育的表型，富含自我抑制 KIR 的表达， 代表我们出版物中描述的 CMV 感染小鼠中的记忆 NK 细胞的人类等效物。 研究小组确定，在 UCBT 后，这些适应性 NK 细胞具有持续存在的呼吸效应功能 我们广泛的初步数据表明，NKG2C 并不是 CMV 诱导的唯一标记物。 我们鉴定出选择性缺乏近端信号分子的 NK 细胞的扩增。 重新激活 CMV 的 UCBT 接受者中的 FcεR1γ、EAT-2 和 SYK 单独或组合。 细胞在表观遗传学上已做好准备，以增强细胞因子的产生、存活和增加 mTOR 的表达 此外，它们在功能上专门用于抗体依赖性细胞毒性。 (ADCC) 到 CD16 我们将转化这项研究来开发最少的操作方法来激活。 NK 细胞并延长其存活时间，例如与 IL-15、IL-12 和 IL-18 进行隔夜孵育。 还开发了利用“现成”激活/靶向使 NK 细胞具有抗原特异性的策略 我们的总体假设是，适应性 NK 细胞可以被激活并靶向 诱导抗原特异性杀伤以预防或治疗 UCBT 后的复发。在 SA1 中，我们将评估临床效果。 通过分析来自我们成熟临床生物样本库的样本，了解 IL-15 信号传导对适应性 NK 细胞的影响 我们还将对接受非治疗的血液恶性肿瘤患者进行临床试验。 这些试验的主要目的是安全诱导激活的适应性扩张。 在 SA2 中，将研究 NK 细胞的激活和抗原靶向，以预防复发。 AML 异种模型选择第 3 年进入临床测试的最佳策略。这些目标 方法包括 1) IL-15/IL-15Rα-Fc 和抗 CD16x33 BiKE；2) IL-15/IL-15Rα-Fc-抗 CD33 复合物； 或3) IL-15/IL-15Rα-Fc和抗CD16xPR1 BiKE。