Utilization of molecular targeted radionuclides to prime immune responses at local and distant metastatic tumor sites

摘要 结合局部放射治疗和全身免疫治疗，以产生远位肿瘤反应， 远距离未照射部位一直是放射免疫治疗的“圣杯”。临床前数据表明， 放射和全身免疫疗法可以结合起来，以提供增强的反应，但翻译 进入临床环境要困难得多。这些喜忧参半的结果可能部分解释如下： 高肿瘤负荷或远处疾病的免疫抑制作用，以及许多癌症 免疫原性差或“感冒”，对免疫治疗的应答率低。因此， 该提案旨在增强转移性乳腺癌临床前模型中免疫疗法治疗的功效， 免疫学上的“冷”肿瘤对传统的系统性免疫疗法，如免疫治疗， 检查点抑制剂（ICI，例如抗CTLA 4、抗PD 1），与我们目前的目标患者最相似 今天，我们正在努力改善结果。因此，我们开发了一种转移模型， 免疫学上的“冷”黑色素瘤，具有大的已建立的原发性肿瘤，庞大的继发性疾病部位，以及 远距离的疾病部位，类似于我们需要在诊所治疗的患者的疾病负担类型。我们 初步数据显示，为了优化该模型中的治愈率，我们需要一种三管齐下的方法。一是 使用强局部原位疫苗方案（ISV），包括外部放射治疗（12戈伊x 1）， 肿瘤内注射肿瘤特异性抗体和IL 2。仅次于全身性疾病的主要远端疾病 免疫疗法治疗我们利用一种新的分子靶向放射治疗（MTRT）剂，NM 600，它是一种 已螯合至86/90 Y的二羟烷基磷酸胆碱分子。这些MTRT特工此前曾 在几乎所有测试的哺乳动物肿瘤细胞（包括> 70%的肿瘤细胞）中显示具有选择性肿瘤摄取 线和在各种临床试验中的患者中）。最后，我们将利用系统性ICI继续进行强大的自适应 免疫激活反应和抑制逃逸机制。我们的初步数据显示， 联合治疗在治疗免疫学“感冒”中的局部、远处和转移性疾病中是有效的。 对ICI没有反应的黑色素瘤模型为了实现本研究的目的，我们将：1）扩展我们的初步研究， 显示MTRT摄取到远处疾病部位并计算肿瘤剂量的数据2）证明了 的MTRT调节肿瘤微环境，在远处和本地网站，以提高免疫治疗的功效， 反应，以及3）在各种“冷”肿瘤模型如黑色素瘤中测试这种治疗方法的功效 (B78)、神经母细胞瘤（NXS 2）、头颈部癌（MOC 2）、乳腺癌（4 T1）和自发性 转基因黑素瘤模型。通过这一建议获得的见解和知识应使我们能够提供 有价值的理由将这种治疗转化为患者的临床试验，并可能改善 任何类型的转移性癌症患者。

ABSTRACT Combining local radiation therapy and systemic immunotherapy to produce an abscopal tumor response at a distant unirradiated site has been the “holy grail” of radioimmunotherapy. Preclinical data has shown that radiation and systemic immunotherapy can be combined to provide an enhanced response, however translation into the clinical setting has been much more difficult. These mixed results may partly be explained by immunosuppressive effects of high tumor burden or distant disease as well as the fact that many cancers are poorly immunogenic or “cold” with low response rates to immunotherapeutic treatments. Therefore, the aims of this proposal look to enhance the efficacy of immunotherapy treatments in preclinical models of metastatic immunologically “cold” tumors that don’t respond to traditional systemic immunotherapy such as immune checkpoint inhibitors (ICI, e.g. anti-CTLA4, anti-PD1) and most closely resembles our current target patient population today in whom we are trying to improve outcomes. Therefore, we developed a metastatic model of immunologically “cold” melanoma with a large established primary tumor, bulky secondary disease sites, and distant disease sites that resembles the type of disease burden we need to treat in our patients in the clinic. Our preliminary data shows that to optimize cure rates in this model we require a three-prong approach. First, we utilize a strong local in situ vaccine regimen (ISV) consisting of external beam radiation therapy (12 Gy x 1) and intratumoral injection of a tumor specific antibody and IL2. Next to prime distant disease for systemic immunotherapy treatment we utilize a novel molecular targeted radiotherapy (MTRT) agent, NM600, which is a diapeutic alkylphosphocholine molecule that has been chelated to 86/90Y. These MTRT agents have previously been shown to have selective tumor uptake in virtually all mammalian tumor cells tested (including > 70 tumor lines and in patients across various clinical trials). Lastly, we will utilize systemic ICI to continue a robust adaptive immune activation response and suppress escape mechanisms. Our preliminary data shows that this combination treatment is effective in curing local, distant, and metastatic disease in an immunologically “cold” melanoma model that doesn’t respond ICI alone. For the aims of this study we will: 1) expand on our preliminary data showing uptake of MTRT to sites of distant disease and calculate tumor dosimetry 2) demonstrate the ability of MTRT to modulate a tumor microenvironment at both distant and local sites to enhance the efficacy of immune response, and 3) test the efficacy of this treatment approach in a variety “cold” tumor models such as melanoma (B78), neuroblastoma (NXS2), head and neck cancer (MOC2), breast cancer (4T1), and a spontaneously arising transgenic melanoma model. The insights and knowledge gained by this proposal should allow us to provide valuable justification to translate this treatment to clinical testing in patients and potentially improve outcomes in patients with any type of metastatic cancer.