Enhancing CAR T therapy in multiple myeloma

工作总结 我们的长期目标是开发新的方法来增强嵌合抗原受体(CAR)T细胞的疗效 心理治疗。针对B细胞成熟抗原(BCMA)的CAR T细胞疗法在治疗中显示出巨大的前景 复发和/或难治性(RR)多发性骨髓瘤(MM)。然而，即使有相对较短的随诊复发， 最终发生在一半以上的患者中，中位无进展生存期仅为11.8个月(Raje et 艾尔N Engl J Med 2019；380：1726)。更好地了解骨髓瘤复发和耐药的机制 TO CAR T疗法是迫切需要的，并将导致CAR T疗法的改进。髓系来源的抑制细胞 (MDSCs)是由单核细胞MDSCs和粒细胞MDSCs组成的异质性细胞群体。 MDSCs抑制T细胞功能，被认为在CAR T治疗抵抗/复发中发挥重要作用。这个 在实体瘤模型中，增加MDSC耗竭治疗可提高CAR T疗效(Long等人。癌症免疫 Res 2016；4：869)。最近我们发现RRMM患者的Gr-MDSCs显著升高。 此外，我们发现在可移植的多发性骨髓瘤中，MDSCs的增加与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)基因敲除相比 小鼠，鞘氨醇激酶2(SK2)基因敲除的小鼠在注射了 VK*MYC骨髓瘤细胞，MDSCs数量明显减少。此外，用一种 特异性SK2抑制剂(ABC294640，YELIVA？)可消除人和小鼠的MDSCs。ABC294640显示 在我们最近完成的RRMM患者的I期研究中，安全性极高(NCT02757326)。这个 该应用的目的是确定SK2抑制和CAR T治疗联合治疗的疗效。 MM的治疗我们的中心假设是SK2抑制剂和CAR T治疗的结合将增强 通过减少骨髓间充质干细胞的数量来改善CAR T治疗的疗效和持续时间。我们有三个具体目标。 目的1确定SK2抑制剂(ABC294640)与CAR-T联合治疗的体内疗效。 一种完全免疫活性的同基因骨髓瘤CAR-T治疗小鼠模型。我们将确定其疗效。 将ABC294640与小鼠BCMA靶向CAR T细胞治疗相结合。目标2是确定 SK2调控MDSCs的机制。我们将确定SK2对MDSC分化的影响 和功能，并在S1P-STAT3/HDAC-1/2-ROR-GT通路上。目标3是测量数字和功能 恶性血液病患者接受CAR治疗后MDSCs随时间的变化及其相关性研究 MDSCs与疾病复发/对CAR-T治疗耐药之间的关系。我们的研究是创新的，因为它 代表着对现状的新的实质性的背离和重大进步，通过理解 MDSCs和SK2在CAR治疗中的作用我们的研究将从根本上增进我们对CAR T的了解 耐药和复发，并对MM患者的护理和预后产生积极的转化影响。

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.