Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response

项目摘要/摘要 我们的目标是提高转移性癌症的治愈率。为了实现这一点，我们提出了一种组合模式 在所有肿瘤部位刺激和多样化内源性抗肿瘤免疫反应以识别的方法 并以防止复发和长期无癌生存的方式摧毁肿瘤细胞。 免疫检查点抑制物(ICI；如抗PD-L1)是一类调节免疫的免疫疗法 阻断T细胞表面特异性抑制性受体-配体相互作用对肿瘤的耐受性 从而克服T细胞抑制或衰竭。在免疫“热”肿瘤患者中，特征是 通过预先存在但已耗尽的抗肿瘤免疫反应，ICIS可以恢复抗肿瘤免疫的效果 反应，有时导致肿瘤完全和持久的消退。然而，ICIS尚未显示出临床特征 有益于以低水平T细胞浸润性为特征的免疫“感冒”癌症的治疗 突变负担低，几乎没有突变产生的新抗原。克服免疫疗法的治疗 针对免疫冷肿瘤造成的障碍，我们建议将ICIS的全身给药与全身给药结合起来 通过靶向放射性核素治疗(TRT)进行放射治疗。到目前为止，几乎所有的组合方法 放射治疗和免疫治疗使用的是外照射(EBRT)，它能促进肿瘤免疫。 通过激活I型干扰素(干扰素)反应进行细胞浸润。EBRT在多发肿瘤中的应用 部位或全身(以放射学上隐蔽的或微观的疾病为靶点)将导致令人望而却步 毒性，包括淋巴细胞减少症。TRT是一种将治疗性放射性核素输送到肿瘤的系统性方法， 这为将免疫调节辐射输送到转移性肿瘤部位提供了另一种选择 导致免疫抑制。威斯康星大学麦迪逊分校的Weichert实验室开发了一种新的 一类TRT，称为NM600，是一种烷基磷胆碱类似物，在几乎 任何部位的任何肿瘤类型。我们的广泛假设是，放射性核素的独特物理性质(例如 发射类型、线性能量转移、半衰期、组织范围)对TRT的免疫调节有不同的影响。在……里面 本研究中，放射核素的α(225Ac)和β(90Y)粒子的免疫调节能力将是 直接比较。在一个建立在莫里斯和魏切特夫妇正在进行的合作进展的项目中 实验室，我们现在将确定TRT与免疫疗法相结合的放射性核素特异性效力以增强 对免疫寒冷肿瘤的免疫反应。在小鼠模型中，我们将：1)扩展初步 数据显示TRT和ICI的联合治疗有很强的协同作用，2)评估TRT的治疗机制 和ICI利用225Ac-和90Y-NM600的固有特性，专注于I型干扰素反应激活和3) 研究两种不同的放射性核素与ICI联合应用可能增强的肿瘤反应。这个 在这些研究中开发的见解和治疗方案应该能够快速转化为临床测试 患者和潜在的任何类型的转移性癌症。

Project Summary/Abstract We aim to improve the cure rates for metastatic cancers. To achieve this we propose a combined modality approach to stimulate and diversify an endogenous anti-tumor immune response at all tumor sites to recognize and destroy tumor cells in a manner that will prevent recurrence and enable long-term cancer free survival. Immune checkpoint inhibitors (ICI; e.g. anti-PD-L1), are a class of immunotherapies that modulate immune tolerance of a tumor by blocking specific inhibitory receptor-ligand interactions on the surface of T cells and thereby overcoming T cell inhibition or exhaustion. In patients with immunologically “hot” tumors, characterized by a pre-existing but exhausted anti-tumor immune response, ICIs can restore efficacy to the anti-tumor immune response, sometimes resulting in complete and durable tumor regression. However, ICIs have not shown clinical benefit in the treatment of immunologically “cold” cancers that are characterized by low levels of T cell infiltrate and low mutation burden resulting in few mutation-created neo-antigens. To overcome immunotherapy treatment barriers posed by immunologically cold tumors, we propose to combine systemic delivery of ICIs with systemic delivery of radiation by targeted radionuclide therapy (TRT). To date, nearly all approaches to combining radiation and immunotherapy have used external beam radiotherapy (EBRT), which promotes tumor immune cell infiltration through activation of type I interferon (IFN) responses. Administration of EBRT to multiple tumor sites or to the whole body (to target radiographically occult or microscopic disease) would result in prohibitive toxicity, including lymphopenia. TRT is a systemic method of delivering a therapeutic radionuclide to a tumor, which poses an alternative option for delivery of immunomodulatory radiation to metastatic tumor sites without causing immunosuppression. The Weichert lab at the University of Wisconsin-Madison has developed a novel class of TRT, known as NM600, an alkylphosphocholine analog that is selectively taken up and retained in nearly any tumor type in any location. Our broad hypothesis is that unique physical properties of radionuclides (e.g. emission type, linear energy transfer, half-life, tissue range) differentially impact immunomodulation by TRT. In this study, the immunomodulatory capacity of alpha- (225Ac) and beta- (90Y) particle emitting radionuclides will be compared directly. In a project that builds upon the ongoing collaborative progress of the Morris and Weichert labs, we will now determine the radionuclide-specific potency of combining TRT with immunotherapy to enhance the immune response against immunologically cold tumors. In murine models, we will: 1) expand on preliminary data showing potent synergy with the combination of TRT and ICI, 2) evaluate therapeutic mechanisms of TRT and ICI using the intrinsic properties of 225Ac- and 90Y-NM600, focusing on type I IFN response activation and 3) investigate potential enhanced tumor responses with the combination of two distinct radionuclides with ICI. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients and potentially for any type of metastatic cancer.