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，并且仍然是导致卵巢癌的主要原因 美国妇科癌症死亡人数。因此，对新的治疗方案的需求亟待满足。 嵌合抗原受体 (CAR) T 细胞疗法已导致一些血液癌症发生范式转变，但 实体瘤的疗效仍然有限，部分原因是缺乏高度特异性的靶点和免疫抑制 在肿瘤微环境（TME）中。此外，制造自体细胞的时间和成本较高 产品，以及与 CAR T 细胞疗法相关的毒性挑战需要通用的新型产品， 安全、有效。人们对使用自然杀伤 (NK) 细胞进行 CAR 工程越来越感兴趣，因为它们具有 具有杀死肿瘤细胞的先天能力，并且它们在同种异体环境中是安全的。在一项首次人体研究中，我们的团队 显示了针对 B-患者的脐带血 (CB) 衍生的 CAR-NK 细胞靶向 CD19 的安全性和有效性 淋巴系统恶性肿瘤。该提案旨在建立在这个平台上开发下一代NK细胞 通过最佳共刺激增强 NK 细胞效力和持久性来治疗卵巢癌 信号传导、细胞因子装甲和检查点抑制。我们已经确定 TROP2 是一种有前途的治疗方法 靶向铂耐药性卵巢癌，并开发了一种通过基因靶向 TROP2 的新策略 用逆转录病毒载体修饰 CB-NK 细胞，该载体包含 (i) 人源化 RS7 单链的基因 靶向 TROP2 的可变片段； (ii) DAP10 作为 NK 特异性共刺激结构域； (iii) IL-15支持 它们的生存和增殖； (iv) 诱导型 caspase-9 (iC9) 作为安全开关 (iC9/TROP2CAR/IL-15)。我们的 初步数据显示了该方法在体外和体内的有效性和安全性，并支持其转化为 诊所。此外，我们还开发了一种强有力的策略来冷冻保存 CAR-NK 细胞，以便 生成现成的工程 NK 细胞生物库，可以在床边解冻并输注，从而 降低成本并增加可及性。最后，我们设计了一种针对免疫的新策略 代谢检查点 CREM 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 将大大改善治疗结果 铂耐药性卵巢癌，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。我们将在三个具体目标中检验我们的假设： 在目标 1 中，我们将 进行 I/II 期临床试验，测试腹腔注射 iC9/TROP2CAR/IL- 的安全性和有效性 TROP2+ 铂耐药性卵巢癌患者的 15 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表征 过继转移的 CAR-NK 细胞、它们与腹膜 TME 的相互作用以及关键功效机制 和阻力。在目标 3 中，我们将进行机制研究，以阐明 CREM 缺失如何增强 CAR-NK 细胞的代谢适应性和 IND 前研究，为下一代临床研究做准备。