Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies

摘要 我们正在开发一种综合治疗方法来根除转移性癌症 免疫“冷”，对免疫检查点抑制(ICI)无反应。使用一种“原位疫苗” 方案包括12Gy射线外照射(EBRT)和瘤内注射(IT) 肿瘤特异性抗体(MAb)IL2，我们已经根除了小鼠孤立的、大的、冷的同基因肿瘤。此入站 原位疫苗将靶向肿瘤转化为增强的肿瘤抗原提呈焦点，导致 增加T细胞的渗透和强大的T细胞记忆。然而，出现了一种相同但未经治疗的 小鼠另一侧的第二个肿瘤(2°)抑制了这种治疗的效果，阻止了肿瘤的根除 EBRT单抗-IL2治疗原发性(1°)肿瘤。在这种情况下，未经治疗的2°肿瘤会导致肿瘤- 1°肿瘤对EBRT-IT单抗-IL2的特异性免疫无反应性。我们把这称为伴随现象 免疫耐受(CIT)。我们可以克服CIT，并通过给予IT单抗-IL2到1°来消除这两种肿瘤 肿瘤和EBRT对1°和2°肿瘤均有效。2°肿瘤仅给予2GyEBRT即可克服 引用如上临床上，将EBRT(即使是低剂量)输送到所有转移性疾病部位都是有问题的，但这可能 使用分子靶向放射治疗(MTRT)可以有效地实现这一目标。MTRT越来越多地进入 临床肿瘤学实践和我们的UW团队领导了一种新型MTRT的临床前和临床测试 使用烷基磷胆碱(APCH)类似物，选择性地向体内的癌症传递辐射。这些节目展示了 几乎所有被测试的哺乳动物肿瘤细胞和肿瘤部位(包括&gt；90肿瘤)的肿瘤选择性摄取 在不同临床试验的患者中)。在同基因小鼠黑色素瘤模型中，我们观察到 系统管理的ICI和使用我们的下一代APC提供的MTRT之间的强大协同 模拟，90Y-NM600。在一个建立在我们的多学科持续合作进展的项目中 团队，我们现在将系统地优化MTRT和免疫疗法的结合效力，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MTRT和ICI的组合具有强大的协同作用，2)评估 MTRT克服CIT，增强多发肿瘤患者的全身抗肿瘤免疫反应 单独使用原位疫苗(EBRT-mAb-IL2)或与ICI联合治疗。因为 小鼠模型不能复制人类转移性癌症的大小和空间分布，因为这些 影响MTRT剂量学的因素很多，我们将在原位测试MTRT的免疫调节作用 大品种伴犬(宠物狗)自然发生转移性黑色素瘤的疫苗。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 在患者身上进行测试，并可能检测任何类型的转移性癌症。

ABSTRACT We are developing a combined modality therapeutic approach to eradicating metastatic cancers that are immunologically “cold” and do not respond to immune checkpoint inhibition (ICI). Using an “in situ vaccine” regimen consisting of 12 Gy focal external beam radiation therapy (EBRT) and intratumoral (IT) injection of tumor-specific antibody (mAb) + IL2, we have eradicated solitary, large, cold syngeneic tumors in mice. This in situ vaccine converts the targeted tumor into a focus of enhanced tumor antigen presentation resulting in increased T-cell infiltration and potent T-cell memory. However, the presence of an identical but untreated second tumor (2°) on a mouse’s opposite flank inhibits the effect of this treatment, preventing eradication of the primary (1°) tumor treated with EBRT + IT mAb-IL2. In this setting, the untreated 2° tumor causes tumor- specific immune unresponsiveness to EBRT + IT mAb-IL2 at the 1° tumor. We refer to this as concomitant immune tolerance (CIT). We can overcome CIT, and eliminate both tumors by giving IT mAb-IL2 to the 1° tumor and EBRT to both the 1° and 2° tumors. Delivering as little as 2 Gy EBRT to the 2° tumor can overcome CIT. Clinically, delivery of EBRT (even low dose) to all sites of metastatic disease is problematic, but this can effectively be achieved using molecular targeted radiation therapy (MTRT). MTRT is increasingly entering clinical oncology practice and our UW team has led preclinical and clinical testing of a novel class of MTRT using alkylphosphocholine (APCh) analogs that selectively deliver radiation to cancers in vivo. These show tumor-selective uptake in virtually all mammalian tumor cells and tumor locations tested (including > 90 tumor lines and in patients across various clinical trials). In a syngeneic murine melanoma model, we have observed a potent synergy between systemically administered ICI and MTRT delivered using our next-generation APC analog, 90Y-NM600. In a project that builds upon the ongoing collaborative progress of our multidisciplinary team, we will now systematically optimize the potency of combining MTRT 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 MTRT and ICI, 2) evaluate the capacity of MTRT to overcome CIT and enhance systemic anti-tumor immune response in the setting of multiple tumors where one is treated with in situ vaccine (EBRT + IT mAb-IL2) alone or in combination with ICI. Because murine models do not replicate the size and spatial distribution of human metastatic cancer and because these factors strongly influence the dosimetry of MTRT, we will test the immunomodulatory effects of MTRT + in situ vaccine in large breed companion canines (pet dogs) with naturally occurring metastatic melanoma. 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.