Enhancing CAR T therapy in multiple myeloma

增强多发性骨髓瘤的 CAR T 疗法

• 批准号: 10588210
• 负责人: Yubin Kang
• 金额: $ 18.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588210
• 关键词: American Society of Clinical Oncology; Animal Model; Antigen Targeting; Antigens; Automobile Driving; Award; B cell therapy; B-Lymphocytes; CAR T cell therapy; Caring; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Clinical; Clinical Trials; Data; Development; Disease; Goals; Hematologic Neoplasms; Histone Deacetylase; Human; Immune system; Immunocompetent; In Vitro; Incidence; Knockout Mice; Knowledge; Malignant Neoplasms; Measures; Mission; Modeling; Molecular; Monoclonal Antibodies; Multiple Myeloma; Mus; Myeloid-derived suppressor cells; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacological Treatment; Plasma Cells; Play; Population; Population Heterogeneity; Progression-Free Survivals; Proteasome Inhibitor; Public Health; Recurrent disease; Refractory; Relapse; Research; Resistance; Resistance development; Role; SPHK1 enzyme; STAT3 gene; Safety; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic Agents; Time; Transplantation; Treatment Efficacy; United States; United States National Institutes of Health; Work; chimeric antigen receptor; chimeric antigen receptor T cells; disability; effective therapy; efficacy evaluation; follow-up; genetic approach; granulocyte; immune modulating agents; improved; improved outcome; in vivo; inhibitor; innovation; meetings; monocyte; mouse model; novel strategies; novel therapeutics; phase 1 study; pomalidomide; pre-clinical; response; sphingosine kinase; translational impact

SUMMARY OF WORK Our long-term goal is to develop novel approaches to enhance the efficacy of chimeric antigen receptor (CAR) T therapy. CAR T cell therapy targeting B-cell maturation antigen (BCMA) has shown great promise in the treatment of relapsed and/or refractory (RR) multiple myeloma (MM). However, even with relatively short follow-up relapse eventually occurs in over half of all patients with a median progression-free survival of only 11.8 months (Raje et al. N Engl J Med 2019; 380:1726). A better understanding of the mechanisms of myeloma relapse and resistance to CAR T therapy is urgently needed and will lead to improved CAR T therapy. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells consisting of monocytic MDSCs and granulocytic MDSCs. MDSCs inhibit T cell function and are thought to play an important role in CAR T therapy resistance/relapse. The addition of MDSC depleting therapy increases CAR T efficacy in solid tumor models (Long et al. Cancer Immunol Res 2016; 4:869). Recently we have found that patients with RRMM had significantly elevated Gr-MDSCs. Additionally, we found that an increase of MDSCs correlated with the development of MM in a transplantable VK*MYC mouse myeloma model. Interestingly, compared to wild-type or sphingosine kinase 1 (SK1) knockout mice, sphingosine kinase 2 (SK2) knockout mice were completely free of myeloma after being injected with VK*MYC myeloma cells and showed significantly reduced numbers of MDSCs. Furthermore, treatment with a specific SK2 inhibitor (ABC294640, YELIVAÒ) eliminated both human and mouse MDSCs. ABC294640 showed an excellent safety profile in our recently completed phase I study in patients with RRMM (NCT02757326). The objective of this application is to determine the efficacy of combining SK2 inhibition with CAR T therapy in the treatment of MM. Our central hypothesis is that the combination of SK2 inhibitor and CAR T therapy will enhance the response and duration of the CAR T therapy by reducing the number of MDSCs. We have three specific aims. Aim 1 is to determine the efficacy of the combination of SK2 inhibitor (ABC294640) and CAR T therapy in vivo in a fully immunocompetent, syngeneic myeloma CAR T therapy mouse model. We will determine the efficacy of combining ABC294640 with mouse BCMA-targeted CAR T cell therapy in vivo. Aim 2 is to determine the mechanisms through which SK2 regulates MDSCs. We will determine the effects of SK2 on MDSC differentiation and function and on the S1P-STAT3/HDAC-1/2- ROR-gt pathway. Aim 3 is to measure the number and function of MDSCs over time in hematologic malignancy patients treated with CAR T therapy and determine the correlation between MDSCs and disease relapse/resistance to CAR T therapy. Our research is innovative, because it represents a new and substantive departure and significant advance from the status quo by understanding the roles of MDSCs and SK2 in CAR T therapy. Our study will fundamentally advance our knowledge of CAR T resistance and relapse, and have a positive translational impact on the care and outcomes of patients with MM.

工作摘要 我们的长期目标是开发新的方法来提高嵌合抗原受体（CAR）T的效率 治疗。靶向B细胞成熟抗原（BCMA）的CAR T细胞疗法在治疗方面表现出巨大的希望 中继和/或耐火（RR）多发性骨髓瘤（mm）。但是，即使随访相对较短 甚至在所有中位无进展生存期仅11.8个月的患者中，甚至发生 al。 N Engl J Med 2019; 380：1726）。更好地理解骨髓瘤继电器和抗性的机制 迫切需要进行汽车治疗，并将导致改善的汽车治疗。髓样衍生的抑制细胞 （MDSC）是由单核细胞MDSC和粒细胞MDSC组成的细胞的异质群。 MDSC抑制T细胞功能，被认为在耐药性/复发性中起重要作用。这 MDSC耗竭疗法的添加可提高实体瘤模型的CAR T效率（Long等人癌症免疫 Res 2016; 4：869）。最近，我们发现RRMM患者的GR-MDSC显着升高。 此外，我们发现MDSC的增加与可移植中MM的发展相关 VK*MYC小鼠骨髓瘤模型。有趣的是，与野生型或鞘氨醇激酶1（SK1）敲除相比 小鼠，鞘氨醇激酶2（SK2）敲除小鼠被注射后完全没有骨髓瘤 VK*myc骨髓瘤细胞，显示出MDSC的数量显着减少。此外，用 特定的SK2抑制剂（ABC294640，Yelivaò）消除了人类和小鼠MDSC。 ABC294640显示 在我们最近完成的I阶段研究中，对RRMM患者（NCT02757326）的I阶段研究非常出色。这 该应用的目的是确定将SK2抑制与CAR T治疗相结合的有效性 mm的处理。我们的中心假设是SK2抑制剂和CAR T治疗的组合将增强 通过减少MDSC的数量，汽车疗法的反应和持续时间。我们有三个具体的目标。 AIM 1是确定SK2抑制剂（ABC294640）和体内CAR T治疗的效率 一种完全免疫能力的，合成性骨髓瘤T疗法的模型。我们将确定 在体内将ABC294640与小鼠BCMA靶向的CAR T细胞疗法相结合。目标2是确定 SK2调节MDSC的机制。我们将确定SK2对MDSC分化的影响 和功能以及在S1P-Stat3/HDAC-1/2-ROR-GT途径上。 AIM 3是测量数量和功能 通过CAR T治疗治疗的血液系统恶性肿瘤患者的MDSC随着时间的流逝而确定相关性 在MDSC和疾病缓解/对汽车治疗的抵抗之间。我们的研究具有创新性，因为它 通过了解 MDSC和SK2在CAR T疗法中的作用。我们的研究将从根本上提高我们对汽车的了解 抵抗和复发，并对MM患者的护理和结果产生积极的翻译影响。