Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition

项目摘要--项目2 在一个建立在我们多学科团队持续合作进展的项目中，我们将 系统评价协同作用机制，优化治疗方案效果 结合靶向放射性核素治疗(TRT)和免疫检查点抑制(ICI；例如抗PD- 1、抗CTLA-4)增强对转移癌的抗肿瘤免疫应答。中等剂量 (8-12Gy)外照射疗法(EBRT)能够诱导原位疫苗效应，将 靶向肿瘤进入病灶，以增强肿瘤抗原识别。在临床前和临床研究中，这一结果 T细胞受体(TCR)谱系的多样化。因此，在临床前研究中，EBRT改善了 对ICIS的回应。这至少在一定程度上取决于EBRT激活I型干扰素的能力。 受辐射的肿瘤细胞的反应。然而，临床研究尚未确凿地证明从 将EBRT与ICIS相结合，甚至在表明有好处的研究中，很明显，如果我们的目标是 开发一种有效的方法来根除所有癌症患者的转移性疾病。为了追求这样的目标， 我们现在建议评估下一代战略，以利用辐射能力来增强 通过使用TRT将辐射传递到转移性疾病环境中的所有肿瘤部位来响应ICIS。要开始 为了测试这一方法，我们将比较不同TRT试剂1)激活I型干扰素的相对能力 肿瘤细胞的反应，2)增强对ICIS的反应，以及3)增加TCR的多样性和克隆性 肿瘤浸润性淋巴细胞的谱系。我们假设TRT将提高肿瘤的速度和深度 对ICIS的反应，这将与对TCR曲目的影响相关，这取决于能力 TRT通过激活I型干扰素反应来调节肿瘤细胞的免疫敏感性。我们预计TRT 也会导致免疫原性细胞死亡、局部炎症和抑制调节性T细胞的暂时耗尽 来自肿瘤微环境(TME)的细胞(Treg)，以及本P01中的其他项目将研究 机制进一步完善。在这里，我们将比较TRT放射性核素和载体的相对影响，以便 对这些药物和抗肿瘤免疫之间的相互作用有一个基本的了解。在……里面 特别是，我们将评估肿瘤大小、类型和数量以及放射性类型的潜在影响。 衰变产物(如α粒子VSβ粒子VSγ-射线VS俄歇电子)，线性能量转移(LET)，剂量，剂量- 速率和半衰期，以及剂量范围。我们还将检查TRT载体的潜在影响，特别是测试 TRT在机体、肿瘤和亚细胞水平的分布变化如何影响抗肿瘤免疫。这个 在这些研究中形成的见解和治疗方案应该能够迅速转化为临床 对任何类型的转移性癌症患者进行测试，同时启动一代随访 基础和转化性临床前研究。

PROJECT SUMMARY – PROJECT 2 In a project that builds upon the ongoing collaborative progress of our multidisciplinary team, we will systematically evaluate mechanisms of cooperative interaction and optimize the potency of treatment regimens that combine targeted radionuclide therapies (TRT) with immune checkpoint inhibition (ICI; e.g. anti-PD- 1, anti-CTLA-4) to enhance the anti-tumor immune response against metastatic cancers. Moderate dose (8-12 Gy) external beam radiation therapy (EBRT) is capable of eliciting an in situ vaccine effect, converting the targeted tumor into a nidus for enhanced tumor antigen recognition. In preclinical and clinical studies, this results in diversification of the T cell receptor (TCR) repertoire. Consequently, in preclinical studies, EBRT improves the response to ICIs. This is at least in part dependent upon the capacity of EBRT to activate a type I interferon (IFN) response in radiated tumor cells. However, clinical studies have not yet conclusively demonstrated a benefit from combining EBRT with ICIs, and even in studies that suggest a benefit it is clear that more is needed if we aim to develop an effective approach to eradicating metastatic disease for all cancer patients. In pursuit of such a goal, we now propose to evaluate a next generation strategy to leveraging the capacity of radiation to enhance response to ICIs by using TRTs to deliver radiation to all tumor sites in settings of metastatic disease. To begin testing this approach, we will compare the relative capacities of different TRT agents to 1) activate a type I IFN response in tumor cells, 2) augment response to ICIs, and 3) increase the diversity and clonality of the TCR repertoire among tumor infiltrating lymphocytes. We hypothesize that TRT will enhance the rate and depth of response to ICIs and that this will correlated with effects on the TCR repertoire that are dependent on the ability of TRT to modulate tumor cell immune susceptibility by activating a type I IFN response. We expect that TRTs will also elicit immunogenic cell death, local inflammation, and temporary depletion of suppressive regulatory T cells (Tregs) from the tumor microenvironment (TME), and other Projects in this P01 will investigate those mechanisms further. Here, we will compare the relative effects of TRT radionuclides and vectors in order to develop a fundamental understanding of the interactions between these agents and anti-tumor immunity. In particular, we will evaluate the potential impacts of tumor size, type, and number as well as the type of radioactive decay products (e.g. α particle vs β particle vs γ-ray vs Auger electron), linear energy transfer (LET), dose, dose- rate and half-life, and dose range. We will also examine the potential impact of the TRT vector, specifically testing how changes in TRT distribution at the organism, tumor, and subcellular level affect anti-tumor immunity. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients with any type of metastatic cancer while also launching a generation of follow-up basic and translational preclinical studies.