Combining immunotherapy with molecularly targeted radiation therapy

项目摘要/摘要 免疫检查点抑制剂(ICI)在抗去势转移性前列腺癌中的单药活性有限 癌症(MCRPC)，部分与肿瘤浸润性淋巴细胞(TIL)数量相对较多有关 反应性肿瘤类型。放射治疗(RT)可通过以下两种方式增强免疫治疗： 免疫反应和/或重置免疫抑制的肿瘤微环境以增强效应器 功能。了解RT可促进mCRPC免疫治疗的机制具有重要意义 未得到满足的需求。 利用单细胞RNA测序(ScRNAseq)，我们发现外束RT诱导了 前列腺癌肿瘤中原有T细胞克隆与新克隆型的大规模替代 微环境一致的免疫启动。然而，这种治疗也会导致新的髓系状态。 在肿瘤微环境中，这可能介导免疫抑制和抑制新启动的T细胞。 我们假设分子靶向放射配基治疗可以诱导免疫启动，而不需要 诱导与外束辐射相伴的免疫抑制。在前列腺癌中，β- 针对前列腺特异性膜抗原(PSMA)的177Lu-PSMA-617粒子的发射代表着一种 MCRPC的新兴治疗方法。然而，实现放射配基治疗的最佳时间表和形式 最佳的免疫原性仍有待阐明。在目标1中，我们将使用多染色体单细胞分析 (scRNAseq、T细胞受体测序和单细胞蛋白质组学)，以剖析治疗引起的变化 接受治疗的mCRPC患者TME和循环中免疫效应物和调节细胞状态的变化 在我们的1b期试验中，使用培溴利珠单抗和一剂177Lu-PSMA-617。在目标2中，我们将执行 前瞻性研究人员启动的第二阶段临床试验，将培溴利珠单抗与重复剂量的177Lu- PSMA-617，其中在PSA进展到救援时触发后续剂量的177Lu-PSMA-617 抗肿瘤免疫。在目标3中，我们定义了β-(177Lu)粒子与α-(225Ac)粒子的免疫原性影响 放射治疗和外照射治疗，以帮助指导未来的放射免疫治疗试验。 通过这项建议，我们寻求在前列腺癌的免疫治疗领域推进几个重要的方面 方法：1)确定最佳的放射治疗方案和形式，以启动抗肿瘤免疫；2)发展 颗粒酶B-PET功能定量显示免疫反应的新方法，3) 了解治疗诱导的髓系细胞在改变T细胞状态中的作用，4)开发生物标记物 这将使患者能够在未来的试验中进行选择，以及5)确定髓系和/或T细胞的新治疗靶点 增强细胞放射免疫治疗的疗效。

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.