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.

项目总结/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一药物活性有限 癌症（mCRPC），部分与肿瘤浸润淋巴细胞（TIL）数量较少有关， 反应性肿瘤类型。放射治疗（RT）可以通过增强免疫系统的启动来增强免疫治疗。 免疫应答和/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免疫治疗的机制是一个重要的 未满足的需求 使用单细胞RNA测序（scRNAseq），我们发现外部束RT诱导了 前列腺癌肿瘤中用新克隆型大规模替代预先存在的T细胞克隆 微环境一致性免疫启动。然而，这种治疗也会诱导新的骨髓状态 在肿瘤微环境中，可能介导免疫抑制并抑制新引发的T细胞。 我们假设分子靶向放射性配体治疗可以诱导免疫启动， 诱导伴随的免疫抑制，这与外部束辐射有关。在前列腺癌中，β- 靶向前列腺特异性膜抗原（PSMA）的发射177 Lu-PSMA-617的颗粒代表了一种前列腺特异性膜抗原。 mCRPC的新兴治疗。然而，放射性配体治疗的最佳时间表和形式，以实现 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），以剖析治疗诱导的变化 在接受治疗的mCRPC患者的TME和循环中的免疫效应细胞和调节细胞状态 在我们的1b期试验中，使用派姆单抗和一剂177 Lu-PSMA-617。在目标2中，我们将执行 帕博利珠单抗与177 Lu重复给药联合的前瞻性药物启动的2期临床试验- PSMA-617，其中在PSA进展至挽救时触发177 Lu-PSMA-617的后续剂量 抗肿瘤免疫在目标3中，我们定义了β-（177 Lu）与α-（225 Ac）颗粒的免疫原性影响 放射治疗和外束放射治疗，以帮助指导未来的放射免疫治疗试验。 有了这个建议，我们寻求在几个重要的领域推进前列腺癌的免疫治疗。 方法：1）确定最佳的时间表和辐射形式，以引发抗肿瘤免疫，2）开发 一种通过颗粒酶B PET在功能上和定量上可视化免疫应答的新方法，3） 了解治疗诱导的髓样细胞在改变T细胞状态中的作用，4）开发生物标志物 这将使患者在未来的试验中选择，和5）确定新的治疗靶点对骨髓和/或T 细胞，以提高放射免疫治疗的疗效。