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

利用分子靶向放射性核素来引发局部和远处转移肿瘤部位的免疫反应

基本信息

批准号：
10238177
负责人：
Ravi Bhasker Patel
金额：
$ 12.59万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238177
关键词：
4T1 90Y Affect Antibodies Bilateral Biodistribution CRISPR/Cas technology Cancer Model Cells Chelating Agents Clinic Clinical Clinical Trials Combination immunotherapy Combined Modality Therapy Data Disease Disease model Disseminated Malignant Neoplasm Distant Dose External Beam Radiation Therapy Future Gene Expression Genes Goals Head and Neck Cancer Human IL2 gene Image Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Markers Immunologic Memory Immunological Models Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy In complete remission Infiltration Injections Knock-out Knowledge Location Low Dose Radiation MEL Gene Malignant Neoplasms Measures Mediating Modality Modeling Molecular Target Mus Myeloid-derived suppressor cells Neoplasm Metastasis Neuroblastoma Normal tissue morphology Pathway interactions Patients Population Positron-Emission Tomography Pre-Clinical Model Primary Neoplasm Radiation Radiation therapy Radioimmunotherapy Radioisotopes Radionuclide Imaging Radionuclide therapy Regimen Regulatory T-Lymphocyte Site Stimulator of Interferon Genes Systemic disease T cell response T-Cell Receptor T-Lymphocyte Tail Tamoxifen Targeted Radiotherapy Testing Therapeutic Time Tissues Transgenic Organisms Translating Translations Treatment Efficacy Tumor Burden Tumor Tissue Tumor Volume Veins adaptive immunity anti-CTLA4 anti-PD-1 burden of illness cancer cell cancer site checkpoint inhibition curative treatments cytokine dosimetry efficacy study efficacy testing immune activation immunogenic immunoregulation improved improved outcome in situ vaccine indexing insight macrophage malignant breast neoplasm melanoma neoplastic cell novel novel strategies patient population pre-clinical research clinical testing response treatment effect treatment planning treatment strategy tumor tumor growth tumor microenvironment tumor-immune system interactions uptake virtual

项目摘要

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.

抽象的结合局部放射治疗和全身免疫治疗，以产生远隔肿瘤反应临床前数据表明，远处未照射部位一直是放射免疫疗法的“圣杯”。放射治疗和全身免疫治疗可以结合起来以提供增强的反应，但是翻译进入临床环境要困难得多，这些混合结果的部分原因可能是：高肿瘤负荷或远处疾病的免疫抑制作用以及许多癌症是免疫原性差或“冷”，对免疫治疗的反应率低。该提案旨在增强免疫疗法在转移性临床前模型中的疗效免疫学“冷”肿瘤，对传统的全身免疫疗法（例如免疫疗法）没有反应检查点抑制剂（ICI，例如抗 CTLA4、抗 PD1），与我们当前的目标患者最相似因此，我们开发了一个转移模型。免疫学“冷”黑色素瘤，具有较大的原发肿瘤、庞大的继发病变部位，以及远处的疾病部位类似于我们在诊所需要治疗的患者的疾病负担类型。初步数据表明，为了优化该模型的治愈率，我们需要采取三管齐下的方法。利用强大的局部原位疫苗方案 (ISV)，包括外照射放射治疗 (12 Gy x 1) 和瘤内注射肿瘤特异性抗体和 IL2，以预防全身性远处病变。免疫疗法治疗我们使用一种新型分子靶向放射治疗（MTRT）药物 NM600，它是一种这些 MTRT 药物先前已与 86/90Y 螯合。已被证明在几乎所有测试的哺乳动物肿瘤细胞（包括 > 70 种肿瘤细胞）中具有选择性肿瘤摄取最后，我们将利用系统性 ICI 来继续稳健的适应性。我们的初步数据表明，免疫激活反应和抑制逃逸机制。联合治疗可有效治愈免疫“冷”状态下的局部、远处和转移性疾病不单独响应 ICI 的黑色素瘤模型为了本研究的目的，我们将：1）扩展我们的初步研究。显示远处疾病部位 MTRT 摄取并计算肿瘤剂量测定的数据 2) 证明了以下能力 MTRT 可以调节远处和局部的肿瘤微环境，从而增强免疫效果反应，3）测试这种治疗方法在多种“冷”肿瘤模型（例如黑色素瘤）中的功效 (B78)、神经母细胞瘤 (NXS2)、头颈癌 (MOC2)、乳腺癌 (4T1) 和自发发生的癌症通过该提案获得的见解和知识应该使我们能够提供转基因黑色素瘤模型。将这种治疗方法转化为患者的临床测试并可能改善结果的宝贵理由患有任何类型的转移性癌症的患者。