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在一年内产生异常的肿瘤反应 远距离未受照射的部位一直是放射免疫疗法的“圣杯”。临床前数据表明， 放射治疗和系统免疫治疗可以结合起来提供增强的反应，然而翻译 进入临床环境要困难得多。这些好坏参半的结果部分原因可能是 高肿瘤负担或远处疾病的免疫抑制效应，以及许多癌症 免疫原性差或“感冒”，对免疫治疗的反应率低。因此，其目的是 这项建议旨在提高临床前转移模型中免疫治疗的疗效。 免疫“冷”瘤，对免疫等传统系统免疫疗法不起作用 检查点抑制物(ICI，如抗CTLA4、抗PD1)，与我们当前的目标患者最为相似 我们正在努力改善结果的今天的人口。因此，我们发展了一种转移模型 免疫学“冷性”黑色素瘤，原发灶较大，继发部位较大， 与我们需要在诊所治疗的患者的疾病负担类型相似的遥远疾病地点。我们的 初步数据显示，为了在这个模型中优化治愈率，我们需要三管齐下的方法。首先，我们 使用强大的局部原位疫苗方案(ISV)，包括外照射(12Gyx1)和 瘤内注射肿瘤特异性抗体和IL2。仅次于全身性远距离疾病 免疫治疗我们使用一种新的分子靶向放射治疗(MTRT)试剂NM600，它是一种 去势的烷基磷胆碱分子，已被螯合到86/90Y。这些MTRT代理之前 已被证明在几乎所有被测试的哺乳动物肿瘤细胞(包括&gt；70肿瘤)中具有选择性肿瘤摄取 在不同临床试验的患者中)。最后，我们将利用系统ICI来继续进行稳健的自适应 免疫激活反应和抑制逃逸机制。我们的初步数据显示，这 联合治疗在治疗免疫感冒的局部、远处和转移性疾病方面是有效的。 黑色素瘤模型不只对ICI有反应。对于本研究的目标，我们将：1)在初步研究的基础上展开 显示MTRT摄取到远处疾病部位并计算肿瘤剂量的数据2)证明了这种能力 MTRT调节远端和局部肿瘤微环境以增强免疫效果 反应，以及3)在黑色素瘤等各种冷肿瘤模型中测试这种治疗方法的有效性 (B78)，神经母细胞瘤(NXS2)，头颈部癌(MOC2)，乳腺癌(4T1)，以及自发发生的 转基因黑色素瘤模型。这项提案所获得的洞察力和知识应该使我们能够提供 有价值的理由将这种治疗方法转化为患者的临床测试，并有可能改善 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.