Off-the-Shelf Engineered Cord Blood NK Cells for the Treatment of Hematologic Malignancies.

用于治疗血液恶性肿瘤的现成工程脐带血 NK 细胞。

基本信息

批准号：
10247039
负责人：
Katy Rezvani
金额：
$ 49.37万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247039
关键词：
Abnormal Cell Acute Lymphocytic Leukemia Address Adoptive Cell Transfers Adoptive Transfer Advanced Malignant Neoplasm Affect Allogenic Autologous B lymphoid malignancy B-Cell Leukemia Bone Marrow CASP9 gene CD19 Antigens CD19 gene CD28 gene CISH gene Cancer Patient Cell Proliferation Cell Survival Cell Therapy Cells Chronic Lymphocytic Leukemia Clinic Clinical Clinical Research Clinical Trials Clinical trial protocol document Cytokine Signaling Data Development Disease Dose Effectiveness Engineering Generations Genes Genetic Genetic Engineering Goals Hematologic Neoplasms Homing Immune Infusion procedures Interleukin-12 Interleukin-15 Interleukin-18 Laboratories Link Logistics Lymphocyte Lymphoma Malignant Neoplasms Malignant lymphoid neoplasm Marrow Measurement Mediating Methods Mus NK cell therapy Natural Killer Cells Non-Hodgkin&apos s Lymphoma Patient-Focused Outcomes Patients Peripheral Pharmacology Phase I/II Clinical Trial Production Proliferating Property Proteins Protocols documentation Refractory Relapse Reporting Research Retroviral Vector Ribonucleoproteins Risk Safety Sampling Signal Transduction Source Specificity Suppressor of Cytokine Signaling Family Protein T-Lymphocyte Testing Therapeutic Toxic effect Translations Tumor Immunity Umbilical Cord Blood base cancer cell cancer therapy cellular transduction chimeric antigen receptor clinical application conventional therapy cytokine cytokine release syndrome design first-in-human genetically modified cells graft vs host disease immune function improved improved outcome in vivo leukemia leukemia/lymphoma member mouse model next generation novel novel strategies pre-clinical receptor refractory cancer response safety testing success suicide gene targeted treatment tumor

项目摘要

ABSTRACT / SUMMARY Despite reports of the strong killing function of NK cells more than four decades ago, adoptive therapy strategies to exploit this property against late-stage cancer cells have had limited success in the clinic. A major obstacle to translation has been the lack of reliable methods to enhance the inadequate persistence and reduced activity of NK cells after their infusion into patients. Thus, the long-term goal of Project 3 is to devise novel adoptive cell-based therapies for advanced B-lymphoid malignancies (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma). The central hypothesis is: (i) the killing function of cord blood (CB)-derived NK cells against hematologic cancers can be substantially enhanced with minimal adverse toxicity, including graft-vs.-host disease, by genetically modifying the cells to express a CD19- specific chimeric antigen receptor (CAR), a suicide gene (inducible caspase-9, or iC9) and the IL-15 cytokine to support NK cell proliferation and durability; and ( ii ) it may be feasible to boost this activity by inhibiting the CISH gene, thus abolishing a pivotal cytokine signaling checkpoint in NK cells and making it possible to consider the use of lower doses of cell therapy without loss of efficacy. This combined strategy, based on our recent preliminary findings as well as the transformative successes with CAR.CD19-redirected T cells, will be pursued in three specific aims. In Aim 1, a first-in-human phase I/II clinical trial, we will evaluate the safety and antitumor activity iC9/CAR.19/IL15-transduced CB-NK cells in 36 patients with advanced leukemia or lymphoma. Aim 2 seeks to track the in vivo fate of the transduced cells described above and correlate the findings with disease responses recorded in Aim 1. This approach will enable us to address several fundamental issues that have been persistent barriers to more effective modes of adoptive NK cell therapy for patients with cancer. Finally, Aim 3 will target CIS, a cytokine signaling checkpoint in NK cells, to further improve the therapeutic potential of our strategy. If we succeed in avoiding toxicity (cytokine release syndrome, for example) that may be associated with targeted therapies of this type, our project will mark a clear advance in the development of novel cellular treatments for cancer.

摘要/总结尽管四十多年前就有报道称 NK 细胞具有强大的杀伤功能，但过继疗法利用这种特性对抗晚期癌细胞的策略在临床上取得的成功有限。一个专业翻译的障碍在于缺乏可靠的方法来增强持久性和有效性 NK细胞输注到患者体内后活性降低。因此，项目 3 的长期目标是设计针对晚期 B 淋巴恶性肿瘤（例如急性淋巴细胞白血病）的新型过继细胞疗法白血病、慢性淋巴细胞白血病和非霍奇金淋巴瘤）。中心假设是：（i）杀戮脐带血 (CB) 衍生的 NK 细胞对抗血液癌症的功能可以显着增强通过对细胞进行基因修饰以表达 CD19-，将不良毒性降至最低，包括移植物抗宿主病特异性嵌合抗原受体 (CAR)、自杀基因（诱导型 caspase-9 或 iC9）和 IL-15 细胞因子支持 NK 细胞增殖和耐久性； (ii)通过抑制 CISH 基因，从而废除了 NK 细胞中关键的细胞因子信号传导检查点，并使考虑使用较低剂量的细胞疗法而不丧失疗效。这一综合战略基于我们最近的初步发现以及 CAR.CD19 重定向 T 细胞的变革性成功，将追求三个具体目标。在目标 1（首次人体 I/II 期临床试验）中，我们将评估安全性和 iC9/CAR.19/IL15转导的CB-NK细胞在36例晚期白血病或淋巴瘤。目标 2 寻求追踪上述转导细胞的体内命运，并将目标 1 中记录的疾病反应结果。这种方法将使我们能够解决几个问题一些基本问题一直是阻碍更有效的过继性 NK 细胞治疗模式的障碍癌症患者。最后，Aim 3 将针对 CIS（NK 细胞中的细胞因子信号传导检查点），以进一步提高我们策略的治疗潜力。如果我们成功地避免毒性（细胞因子释放例如）可能与此类靶向治疗相关，我们的项目将标志着新型癌症细胞疗法的开发取得了明显进展。