Combining immunotherapy with molecularly targeted radiation therapy

免疫治疗与分子靶向放射治疗相结合

基本信息

批准号：
10736873
负责人：
Rahul Aggarwal
金额：
$ 66.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736873
关键词：
Address Alpha Particles Beta Particle Biological Markers Biopsy Specimen Blood specimen Cancer Patient Cells Circulation Clinical Clinical Research Clinical Trials Clone Cells Combination immunotherapy Combined Modality Therapy Development Dose External Beam Radiation Therapy FOLH1 gene Future Granzyme Human Immune Immune checkpoint inhibitor Immune response Immunologics Immunosuppression Immunotherapy In Vitro Malignant Neoplasms Malignant neoplasm of prostate Mediating Modality Molecular Target Multiplexed Ion Beam Imaging Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Outcome Patient Selection Patients Phase Phase II Clinical Trials Phase III Clinical Trials Phase Ib Trial Population Positron-Emission Tomography Pre-Clinical Model Progression-Free Survivals Proteomics Radiation Radiation therapy Radioimmunotherapy Reporting Research Personnel Role Schedule Spatial Distribution T cell receptor repertoire sequencing T cell response T-Lymphocyte Techniques Testing Time Translating Tumor Immunity Tumor-Infiltrating Lymphocytes Visualization advanced prostate cancer anti-PD-1 castration resistant prostate cancer checkpoint inhibition clinical effect clinical efficacy exhaustion immunogenic immunogenic cell death immunogenicity immunoregulation improved improved outcome in vivo men microscopic imaging mouse model multiple omics new therapeutic target novel novel strategies particle patient biomarkers pembrolizumab pre-clinical preclinical study prospective pyrrolidin-3-yl-methanesulfonic acid radioligand radiotracer randomized trial response single cell analysis single-cell RNA sequencing targeted treatment translational study treatment strategy tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICI) have limited single agent activity in metastatic castration resistant prostate cancer (mCRPC), in part related to the low number of tumor-infiltrating lymphocytes (TILs) relative to more responsive tumor types. Radiation therapy (RT) may enhance immunotherapy by either enhancing priming of an immune response and/or resetting the immunosuppressive tumor microenvironment to enhance effector function. Understanding the mechanisms by which RT can enhance immunotherapy in mCRPC is a significant unmet need. Using single cell RNA sequencing (scRNAseq), we have found that external beam RT induces the wholesale replacement of preexisting T cell clones with novel clonotypes in the prostate cancer tumor microenvironment consistent immunologic priming. This treatment, however, also induces novel myeloid states within the tumor microenvironment that may mediate immunosuppression and dampen the newly primed T cells. We hypothesize that molecularly-targeted radioligand therapy may induce immunologic priming without inducing the concomitant immunosuppression seen with external beam radiation. In prostate cancer, the beta- particle emitting 177Lu-PSMA-617, which targets prostate specific membrane antigen (PSMA), represents an emerging treatment of mCRPC. However, the optimal schedule and form of radioligand therapy to achieve an optimal immunogenicity remains to be elucidated. In Aim 1, we will use multi-omic single cell analyses (scRNAseq, T cell receptor sequencing, and single cell proteomics), to dissect the treatment induced changes in immune effectors and regulatory cell states both within the TME and circulation of mCRPC patients treated on our phase 1b trial with pembrolizumab and one dose of 177Lu-PSMA-617. In Aim 2, we will perform a prospective investigator-initiated phase 2 clinical trial combining pembrolizumab with repeated dosing of 177Lu- PSMA-617 where subsequent doses of 177Lu-PSMA-617 are triggered at the time of PSA progression to rescue anti-tumor immunity. In Aim 3, we define the immunogenic impact of beta- (177Lu) vs. alpha- (225Ac) particle emitting therapy and external beam radiation therapy to help guide future trials of radioimmunotherapy. With this proposal, we seek to advance the field of immunotherapy in prostate cancer in several important ways by: 1) determining the optimal schedule and form of radiation to prime anti-tumor immunity, 2) developing a novel approach to functionally and quantitatively visualize immune response through granzyme B PET, 3) understanding the role of treatment-induced myeloid cells in modifying T cell states, 4) developing biomarkers that will enable patient selection in future trials, and 5) identifying novel therapeutic targets on myeloid and/or T cells to enhance the efficacy of radioimmunotherapy.

项目概要/摘要免疫检查点抑制剂（ICI）在转移性去势抵抗性前列腺中的单药活性有限癌症（mCRPC），部分与肿瘤浸润淋巴细胞（TIL）数量相对较少有关反应性肿瘤类型。放射治疗 (RT) 可以通过增强免疫治疗的启动作用来增强免疫治疗。免疫反应和/或重置免疫抑制肿瘤微环境以增强效应功能。了解 RT 增强 mCRPC 免疫治疗的机制具有重要意义未满足的需求。使用单细胞 RNA 测序 (scRNAseq)，我们发现外束 RT 会诱导在前列腺癌肿瘤中用新的克隆型大规模替代现有的 T 细胞克隆微环境一致的免疫启动。然而，这种治疗也会诱导新的骨髓状态肿瘤微环境中可能介导免疫抑制并抑制新启动的 T 细胞。我们假设分子靶向放射配体治疗可能会诱导免疫启动，而无需诱导与外部束辐射一起观察到的伴随免疫抑制。在前列腺癌中，β- 发射 177Lu-PSMA-617 的粒子，靶向前列腺特异性膜抗原 (PSMA)，代表 mCRPC 的新兴治疗方法。然而，实现放射配体治疗的最佳时间表和形式最佳免疫原性仍有待阐明。在目标 1 中，我们将使用多组学单细胞分析（scRNAseq、T 细胞受体测序和单细胞蛋白质组学），剖析治疗引起的变化接受治疗的 mCRPC 患者 TME 和循环中的免疫效应器和调节细胞状态在我们使用 pembrolizumab 和一剂 177Lu-PSMA-617 的 1b 期试验中。在目标 2 中，我们将执行前瞻性研究者发起的 2 期临床试验，将派姆单抗与重复给药 177Lu- 相结合 PSMA-617，其中在 PSA 进展时触发后续剂量的 177Lu-PSMA-617 以进行救援抗肿瘤免疫力。在目标 3 中，我们定义了 β-(177Lu) 与 α-(225Ac) 颗粒的免疫原性影响发射疗法和外束放射疗法有助于指导未来的放射免疫疗法试验。通过这项提议，我们寻求在几个重要的领域推进前列腺癌免疫治疗领域的发展方法：1) 确定最佳的放射计划和形式以激发抗肿瘤免疫力，2) 开发一种通过颗粒酶 B PET 功能性和定量可视化免疫反应的新方法，3) 了解治疗诱导的骨髓细胞在改变 T 细胞状态中的作用，4) 开发生物标志物这将使未来试验中的患者选择成为可能，5) 确定骨髓和/或 T 细胞的新治疗靶点细胞以增强放射免疫治疗的疗效。