Next-Generation Engineered NK Cell Immunotherapy for Ovarian Cancer

下一代卵巢癌工程 NK 细胞免疫疗法

• 批准号: 10709230
• 负责人: Katy Rezvani
• 金额: $ 30.66万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709230
• 关键词: Adoptive Transfer; Allogenic; Autologous; B lymphoid malignancy; B-Lymphocytes; CAR T cell therapy; CASP9 gene; CD19 gene; Cell Therapy; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Cryopreservation; Cyclic AMP; Cyclic AMP Response Element; Data; Dose; Effector Cell; Endowment; Engineering; Event; Exhibits; Gene Deletion; Generations; Genes; Hematologic Neoplasms; Immune Targeting; Immunosuppression; In Vitro; Institutional Review Boards; Interleukin-15; Lactic acid; Lymphoid Cell; Malignant Female Reproductive System Neoplasm; Malignant lymphoid neoplasm; Malignant neoplasm of ovary; Membrane Glycoproteins; Metabolic; NK cell therapy; Natural Killer Cell Immunotherapy; Natural Killer Cells; Normal tissue morphology; Pathway interactions; Patients; Peritoneal; Peritoneal Fluid; Phase I/II Clinical Trial; Platinum; Population; Preparation; Proliferating; Proteomics; Protocols documentation; Publishing; Reporting; Research; Resistance; Retroviral Vector; Safety; Sampling; Secondary to; Signal Transduction; Solid Neoplasm; Specificity; Surface Antigens; T-Lymphocyte; Testing; Time; Toxic effect; Translations; Tumor Antigens; Umbilical Cord Blood; University of Texas M D Anderson Cancer Center; aerobic glycolysis; biobank; cellular transduction; checkpoint inhibition; chimeric antigen receptor; chimeric antigen receptor T cells; cost; cytokine; design; effective therapy; engineered NK cell; first-in-human; fitness; genetically modified cells; graft vs host disease; human study; immune checkpoint; improved outcome; in vivo; innovation; interest; intraperitoneal; lymphoid neoplasm; manufacturing cost; manufacturing process; metabolic fitness; mortality; neoplastic cell; next generation; novel; novel strategies; peripheral blood; pharmacologic; point of care; pre-IND studies; pre-clinical; response; safety testing; success; suicide gene; therapeutic target; transcription factor; transcriptomics; trophoblast; tumor; tumor microenvironment; vector

Project 2 SUMMARY/ ABSTRACT Ovarian cancer is the second most common gynecologic malignancy and remains the leading cause of gynecologic cancer deaths in the US. Therefore, there is a critical unmet need for new treatment options. Chimeric antigen receptor (CAR) T-cell therapy has led to a paradigm shift in some hematologic cancers, but efficacy in solid tumors remains limited, partly due to the lack of highly specific targets and immunosuppression in the tumor microenvironment (TME). Moreover, the time and high cost of manufacturing autologous cell products, and the toxicity challenges related to CAR T-cell therapy call for novel products that are universal, safe, and potent. There is growing interest in using natural killer (NK) cells for CAR engineering since they have an innate ability to kill tumor cells and they are safe in the allogeneic setting. In a first-in-human study, our group showed the safety and efficacy of cord blood (CB)-derived CAR-NK cells targeting CD19 in patients with B- lymphoid malignancies. This proposal aims to build on this platform to develop the next-generation NK cell therapies for ovarian cancer by enhancing NK cell potency and persistence through optimal co-stimulatory signaling, cytokine armoring and checkpoint inhibition. We have identified TROP2 as a promising therapeutic target in platinum-resistant ovarian cancer and developed a novel strategy to target TROP2 by genetically modifying CB-NK cells with a retroviral vector that incorporates the genes for (i) the humanized RS7 single chain variable fragment targeting TROP2; (ii) DAP10 as an NK-specific co-stimulatory domain; (iii) IL-15 to support their survival and proliferation; and (iv) inducible caspase-9 (iC9) as a safety switch (iC9/TROP2CAR/IL-15). Our preliminary data show the efficacy and safety of this approach in vitro and in vivo and support its translation to the clinic. In addition, we have developed a robust strategy to cryopreserve CAR-NK cells, allowing for the generation of a biobank of off-the-shelf engineered NK cells that could be thawed and infused at bedside, thus reducing cost and increasing accessibility. Finally, we have devised a novel strategy to target the immune metabolic checkpoint CREM to modulate the metabolic fitness and potency of CAR-NK cells in the acidic TME. We hypothesize that targeting TROP2 with iC9/TROP2CAR/IL-15 NK cells will greatly improve outcomes for platinum-resistant ovarian cancer and that by targeting the metabolic immune checkpoint CREM we can further enhance the fitness and potency of NK cells. We will test our hypothesis in three specific aims: In Aim 1 we will conduct a Phase I/II clinical trial to test the safety and efficacy of intraperitoneally delivered iC9/TROP2CAR/IL- 15 NK cells in patients with TROP2+ platinum-resistant ovarian cancer (Protocol 2022-0687). In Aim 2 we will apply innovative single-cell proteomic and transcriptomic studies to comprehensively characterize the fate of the adoptively transferred CAR-NK cells, their interaction with the peritoneal TME, and key mechanisms of efficacy and resistance. In Aim 3 we will perform mechanistic studies to elucidate how CREM deletion enhances the metabolic fitness of CAR-NK cells and pre-IND studies in preparation for the next-generation clinical studies.

项目2摘要/摘要 卵巢癌是第二常见的妇科恶性肿瘤，仍然是 美国的妇科癌症死亡。因此，对新治疗方案的需求至关重要。 嵌合抗原受体（CAR）T细胞疗法导致某些血液癌的范式转移，但 实体瘤的功效仍然有限，部分是由于缺乏高度特异性的靶标和免疫抑制 在肿瘤微环境（TME）中。此外，制造自体细胞的时间和高成本 产品，以及与汽车T细胞疗法有关的毒性挑战，要求新的产品通用， 安全，有效。人们对使用天然杀手（NK）细胞进行汽车工程越来越兴趣，因为它们具有 杀死肿瘤细胞的先天能力，在同种异体环境中它们是安全的。在一项人口研究中，我们的小组 显示了针对B-患者的脐带血（CB）衍生的CD19的CAR-NK细胞的安全性和功效 淋巴恶性肿瘤。该建议旨在在此平台上建立开发下一代NK单元 通过最佳共同刺激增强NK细胞效力和持久性，用于卵巢癌的疗法 信号传导，细胞因子装甲和检查点抑制。我们已经将trop2确定为有前途的治疗 靶向铂抗卵巢癌的靶标，并制定了一种新型策略，以基因靶向trop2 用逆转录病毒载体修饰CB-NK细胞，该载体结合了（i）人源化RS7单链的基因 可变片段靶向trop2; （ii）DAP10作为NK特异性共刺激域； （iii）IL-15支持 它们的生存和扩散； （iv）可诱导的caspase-9（IC9）作为安全开关（IC9/trop2car/il-15）。我们的 初步数据显示了这种方法在体外和体内的功效和安全性，并支持其翻译为 诊所。此外，我们已经制定了一种强大的策略来冷冻Reservere Car-nk细胞，从而允许 产生的生物库，可以在床边融化和注入的现成的NK细胞，因此 降低成本并增加可访问性。最后，我们制定了一种针对免疫的新型策略 代谢检查点CREM可调节酸性TME中CAR-NK细胞的代谢适应性和效力。 我们假设用IC9/trop2car/IL-15 NK细胞靶向trop2将大大改善预后 耐铂卵巢癌，并且通过靶向代谢免疫检查点CREM我们可以进一步 增强NK细胞的适应性和效力。我们将以三个具体目的测试我们的假设：在AIM 1中，我们将 进行I/II期临床试验，以测试腹膜内交付的IC9/trop2car/il-的安全性和功效 Trop2+铂抗性卵巢癌患者的15个NK细胞（方案2022-0687）。在目标2中，我们将 应用创新的单细胞蛋白质组学和转录组学研究来全面地表征 采用转移的CAR-NK细胞，与腹膜TME的相互作用以及功效的关键机制 和阻力。在AIM 3中，我们将进行机械研究，以阐明CREM缺失如何增强 汽车NK细胞的代谢适应性和预先研究的研究为下一代临床研究做准备。