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.

项目摘要 尽管化学疗法，放射线和手术，但未分化的多态性肉瘤患者（UPS） 经常遭受无法治愈的疾病复发。免疫检查点封锁是一种有前途的新治疗 UPS患者促进T细胞介导的抗肿瘤免疫的方法。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，可以激发 T细胞抗肿瘤反应并与免疫检查点阻断协同作用。但是RT也可以导致 募集抑制抗肿瘤T细胞反应的免疫抑制，促肿瘤的髓样细胞。这是 在UPS中特别相关，其特征是髓样细胞浸润。候选人 假设重新编程RT诱导的髓样细胞朝着抗原呈递，促炎性 表型将促进UPS中T细胞介导的抗肿瘤免疫。 为了研究该假设 Poly I：C激活双链RNA感应途径，该途径在髓样细胞中高活性。这些 研究将在UPS的鼠模型（AIM 1）以及UPS患者（AIM 2）中进行研究。在AIM 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 诱导髓样细胞。在AIM 2中，候选人评估BO-112，RT和抗PD1免疫的能力 检查点封锁以重塑髓样室并在UPS中提出抗肿瘤T细胞反应 患者参加了机会1阶段临床试验的窗口。这些研究将为您提供关键的见解 RT诱导的髓样子集的可塑性及其在T细胞介导的抗肿瘤免疫中的作用，尤其是在 对BO-112的响应。 候选人是加州大学洛杉矶分校的辐射肿瘤学助理教授 肉瘤。他在肿瘤免疫学和癌症免疫疗法方面的科学记录突出了他 致力于该领域的学术生涯。候选人的时间受到研究和职业的保护 开发（80％的努力），他拥有完成的空间，设备，人员和资源 提出的研究。与他的导师安东尼·里巴斯（Antoni Ribas）和同事威廉·麦克布赖德（William McBride）博士一起 候选人制定了一项全面的职业发展和培训计划，将建立专业知识 四个领域：（1）髓样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，（4）转化阶段1临床试验的行为。这些职业发展活动将支持 提案的完成，并促进向独立科学职业的过渡，以进行基准 床边研究，重点是利用转化免疫学来改变患者的护理 与肉瘤。