Targeting Radiation-Induced Myeloid Cells to Promote T cell Immunity in Undifferentiated Pleomorphic Sarcoma

靶向放射诱导的骨髓细胞促进未分化多形性肉瘤中的 T 细胞免疫

• 批准号: 10745266
• 负责人: Anusha Kalbasi
• 金额: $ 14.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745266
• 关键词: Targeting; Radiation; Induced; Myeloid; Cells

PROJECT SUMMARY Despite chemotherapy, radiation and surgery, patients with undifferentiated pleomorphic sarcoma (UPS) frequently suffer incurable disease relapse. Immune checkpoint blockade is a promising new therapeutic approach for patients with UPS which promotes T cell mediated anti-tumor immunity. Still, the majority of patients do not benefit. Radiation therapy (RT), a cornerstone of preoperative treatment of UPS, can instigate T cell anti-tumor responses and synergize with immune checkpoint blockade. But RT can also result in the recruitment of immunosuppressive, pro-tumor myeloid cells that restrain anti-tumor T cell responses. This is particularly relevant in UPS, which is characterized by a brisk myeloid cell infiltrate. The candidate hypothesizes that reprogramming RT-induced myeloid cells toward an antigen-presenting, pro-inflammatory phenotype will promote T cell mediated anti-tumor immunity in UPS. To investigate the hypothesis the candidate proposes studies using BO-112, a synthetic nanoplexed version of poly I:C that activates double-stranded RNA sensing pathways, which are highly active in myeloid cells. These studies will be conducted in murine models of UPS (Aim 1) as well as in UPS patients (Aim 2). In Aim 1, the candidate will determine the impact of BO-112 on the fate, phenotype and immunomodulatory function of RT- induced myeloid cells. In Aim 2, the candidate evaluates the capacity of BO-112, RT, and anti-PD1 immune checkpoint blockade to remodel the myeloid compartment and instigate anti-tumor T cell responses in UPS patients enrolled on a window of opportunity phase 1 clinical trial. These studies will provide key insight into plasticity of RT-induced myeloid subsets, and their role in T cell mediated anti-tumor immunity, especially in response to BO-112. The candidate is an Assistant Professor in Radiation Oncology at UCLA specializing in the treatment of sarcoma. His scientific track record in tumor immunology and cancer immunotherapy highlights his commitment to an academic career in this field. The candidate's time is protected for research and career development (80% effort), and he has the space, equipment, personnel and resources necessary to complete the proposed studies. Along with his mentor, Dr. Antoni Ribas, and co-mentor, Dr. William McBride, the candidate has developed a comprehensive career development and training plan that will build expertise in four areas: (1) myeloid cell biology and plasticity, (2) genetic mouse models as tools to study sarcoma and the immune system, (3) analysis and interpretation of high-dimensional single cell phenotyping and transcriptomic data, and (4) conduct of a translational phase 1 clinical trial. These career development activities will support completion of the proposal and facilitate the transition to an independent scientific career conducting bench-to- bedside research, with an emphasis on leveraging translational immunology to transform the care of patients with sarcoma.

项目概要 尽管接受化疗、放疗和手术，未分化多形性肉瘤 (UPS) 患者 不治之症经常复发。免疫检查点阻断是一种有前途的新疗法 针对 UPS 患者的方法，可促进 T 细胞介导的抗肿瘤免疫。尽管如此，大多数 患者没有受益。放射治疗 (RT) 是 UPS 术前治疗的基石，可以促进 T 细胞抗肿瘤反应并与免疫检查点阻断产生协同作用。但 RT 也可能导致 募集免疫抑制性促肿瘤骨髓细胞，抑制抗肿瘤 T 细胞反应。这是 尤其与 UPS 相关，其特点是活跃的骨髓细胞浸润。候选人 假设将 RT 诱导的骨髓细胞重编程为抗原呈递、促炎的细胞 表型将促进 UPS 中 T 细胞介导的抗肿瘤免疫。 为了调查这一假设，候选人提出使用 BO-112 进行研究，BO-112 是一种合成的纳米复合版本 Poly I:C 可激活双链 RNA 传感通路，该通路在骨髓细胞中高度活跃。这些 研究将在 UPS 小鼠模型（目标 1）以及 UPS 患者（目标 2）中进行。在目标 1 中， 候选人将确定 BO-112 对 RT-的命运、表型和免疫调节功能的影响 诱导骨髓细胞。在目标 2 中，考生评估 BO-112、RT 和抗 PD1 免疫的能力 UPS 中检查点阻断可重塑骨髓区室并激发抗肿瘤 T 细胞反应 患者参加了机会窗口 1 期临床试验。这些研究将提供重要的见解 RT 诱导的骨髓亚群的可塑性及其在 T 细胞介导的抗肿瘤免疫中的作用，特别是在 对 BO-112 的响应。 该候选人是加州大学洛杉矶分校放射肿瘤学助理教授，专门从事治疗 肉瘤。他在肿瘤免疫学和癌症免疫治疗方面的科学记录凸显了他的 致力于该领域的学术生涯。候选人的研究和职业时间得到保护 开发（80％的努力），并且他拥有完成所需的空间、设备、人员和资源 拟议的研究。与他的导师 Antoni Ribas 博士和共同导师 William McBride 博士一起， 候选人制定了全面的职业发展和培训计划，该计划将培养以下方面的专业知识 四个领域：（1）骨髓细胞生物学和可塑性，（2）遗传小鼠模型作为研究肉瘤和 免疫系统，（3）高维单细胞表型和转录组的分析和解释 数据，以及 (4) 进行转化性 1 期临床试验。这些职业发展活动将支持 完成提案并促进向独立科学职业的过渡，进行实验 床边研究，重点是利用转化免疫学来改变患者的护理 患有肉瘤。