Combining immunotherapy with molecularly targeted radiation therapy

免疫治疗与分子靶向放射治疗相结合

• 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
• 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

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.

项目摘要/摘要 免疫检查点抑制剂（ICI）在转移性cast割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数量少有关（TIL）相对于更多 反应性肿瘤类型。放射疗法（RT）可以通过增强启动的启动来增强免疫疗法 免疫反应和/或重置免疫抑制性肿瘤微环境以增强效应子 功能。了解RT可以增强MCRPC免疫疗法的机制是重要的 未满足的需求。 使用单细胞RNA测序（SCRNASEQ），我们发现外束RT诱导 在前列腺癌肿瘤中，批发替代了先前存在的T细胞克隆 微环境一致的免疫启动。然而，这种治疗也诱导了新型的髓样态 在肿瘤微环境中，可以介导免疫抑制并抑制新底漆的T细胞。 我们假设分子靶向放射性疗法可能会诱导免疫启动 诱导外束辐射看到的伴随免疫抑制。在前列腺癌中，β- 粒子发射177LU-PSMA-617，靶向前列腺特异性膜抗原（PSMA），代表 MCRPC的新兴治疗。但是，放射性疗法的最佳时间表和形式，以实现 最佳免疫原性尚待阐明。在AIM 1中，我们将使用多OMIC单细胞分析 （SCRNASEQ，T细胞受体测序和单细胞蛋白质组学），以剖析处理诱导的变化 在免疫效应子和调节细胞状态中，TME和MCRPC患者的循环 在我们使用pembrolizumab的1B期试验中，一剂为177LU-PSMA-617。在AIM 2中，我们将执行 前瞻性研究者引发的第2阶段临床试验，将pembrolizumab与重复给药177lu- PSMA-617，其中随后的177LU-PSMA-617剂量在PSA进展时触发以营救 抗肿瘤免疫。在AIM 3中，我们定义了β-（177LU）与alpha-（225ac）粒子的免疫原性影响 发射疗法和外束放射疗法，以帮助指导放射免疫疗法的未来试验。 有了这项建议，我们试图在几种重要的 方法：1）确定辐射的最佳时间表和形式，以抗肿瘤免疫，2）开发 一种新颖的方法，可以通过颗粒状B PET进行功能和定量可视化免疫反应，3） 了解治疗诱导的髓样细胞在修饰T细胞态中的作用，4）发展生物标志物 这将使患者在以后的试验中的选择，以及5）确定对髓样和/或T的新型治疗靶标 细胞增强放射免疫疗法的功效。