Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response

靶向放射性核素治疗肿瘤免疫调节和增强免疫治疗反应

基本信息

批准号：
10543064
负责人：
Caroline Paula Anne Kerr
金额：
$ 3.81万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543064
关键词：
90Y Applications Grants CD8-Positive T-Lymphocytes Cancer Patient Canis familiaris Cells Clinical Clinical Trials Combination immunotherapy Combined Modality Therapy Data Dendritic Cells Development Disease Disseminated Malignant Neoplasm Dose Dose Limiting Exhibits External Beam Radiation Therapy Foundations Goals Half-Life Head and Neck Squamous Cell Carcinoma Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Incidence Infiltration Interferon Activation Interferon Type I Ligands Linear Energy Transfer Location Lymphocyte Lymphopenia Malignant Neoplasms Methods Micrometastasis Microscopic Modality Modeling Mus Mutation Neoplasm Metastasis Outcome Pathway interactions Patients Positioning Attribute Predisposition Production Property Proteins Public Health Radiation Radiation therapy Radioisotopes Radionuclide therapy Recurrence Resources Site Spatial Distribution Stimulator of Interferon Genes Surface T cell infiltration T-Lymphocyte Therapeutic Tissues Toxic effect Training Translations Treatment Cost Treatment Protocols Tumor Immunity Tumor Promotion Universities Wisconsin analog anti-CTLA4 anti-PD-L1 anti-tumor immune response cancer therapy cancer type checkpoint therapy chelation comparative exhaust exhaustion experimental study immune cell infiltrate immunoregulation improved insight melanoma mouse model neoantigens neoplastic cell novel novel strategies particle physical property preclinical study prevent professor radiation delivery radiological imaging receptor recruit research clinical testing response synergism treatment response tumor tumor heterogeneity tumor microenvironment

项目摘要

Project Summary/Abstract We aim to improve the cure rates for metastatic cancers. To achieve this we propose a combined modality approach to stimulate and diversify an endogenous anti-tumor immune response at all tumor sites to recognize and destroy tumor cells in a manner that will prevent recurrence and enable long-term cancer free survival. Immune checkpoint inhibitors (ICI; e.g. anti-PD-L1), are a class of immunotherapies that modulate immune tolerance of a tumor by blocking specific inhibitory receptor-ligand interactions on the surface of T cells and thereby overcoming T cell inhibition or exhaustion. In patients with immunologically “hot” tumors, characterized by a pre-existing but exhausted anti-tumor immune response, ICIs can restore efficacy to the anti-tumor immune response, sometimes resulting in complete and durable tumor regression. However, ICIs have not shown clinical benefit in the treatment of immunologically “cold” cancers that are characterized by low levels of T cell infiltrate and low mutation burden resulting in few mutation-created neo-antigens. To overcome immunotherapy treatment barriers posed by immunologically cold tumors, we propose to combine systemic delivery of ICIs with systemic delivery of radiation by targeted radionuclide therapy (TRT). To date, nearly all approaches to combining radiation and immunotherapy have used external beam radiotherapy (EBRT), which promotes tumor immune cell infiltration through activation of type I interferon (IFN) responses. Administration of EBRT to multiple tumor sites or to the whole body (to target radiographically occult or microscopic disease) would result in prohibitive toxicity, including lymphopenia. TRT is a systemic method of delivering a therapeutic radionuclide to a tumor, which poses an alternative option for delivery of immunomodulatory radiation to metastatic tumor sites without causing immunosuppression. The Weichert lab at the University of Wisconsin-Madison has developed a novel class of TRT, known as NM600, an alkylphosphocholine analog that is selectively taken up and retained in nearly any tumor type in any location. Our broad hypothesis is that unique physical properties of radionuclides (e.g. emission type, linear energy transfer, half-life, tissue range) differentially impact immunomodulation by TRT. In this study, the immunomodulatory capacity of alpha- (225Ac) and beta- (90Y) particle emitting radionuclides will be compared directly. In a project that builds upon the ongoing collaborative progress of the Morris and Weichert labs, we will now determine the radionuclide-specific potency of combining TRT 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 TRT and ICI, 2) evaluate therapeutic mechanisms of TRT and ICI using the intrinsic properties of 225Ac- and 90Y-NM600, focusing on type I IFN response activation and 3) investigate potential enhanced tumor responses with the combination of two distinct radionuclides with ICI. 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.

项目概要/摘要我们的目标是提高转移性癌症的治愈率。为了实现这一目标，我们提出了一种联合治疗方法。刺激所有肿瘤部位的内源性抗肿瘤免疫反应并使之多样化的方法，以识别并以防止复发并实现长期无癌生存的方式破坏肿瘤细胞。免疫检查点抑制剂（ICI；例如抗 PD-L1）是一类调节免疫的免疫疗法通过阻断 T 细胞表面的特异性抑制性受体-配体相互作用来实现肿瘤的耐受性克服T细胞抑制或衰竭的免疫学“热”肿瘤患者。通过预先存在但已耗尽的抗肿瘤免疫反应，ICIs 可以恢复抗肿瘤免疫的功效反应，有时会导致肿瘤完全且持久的消退，但是 ICI 尚未显示出临床效果。有益于治疗以 T 细胞浸润水平低为特征的免疫学“冷”癌症和低突变负荷导致很少的突变产生的新抗原克服了免疫疗法的治疗。由免疫学冷肿瘤引起，我们建议将 ICI 的系统递送与系统屏障相结合迄今为止，几乎所有方法都通过靶向放射性核素治疗（TRT）进行放射治疗。放射治疗和免疫治疗均采用外照射放射治疗（EBRT），可促进肿瘤免疫通过激活 I 型干扰素 (IFN) 反应进行细胞浸润。部位或全身（针对放射学上的隐匿性或微观疾病）将导致禁止毒性，包括淋巴细胞减少症，是一种向肿瘤输送治疗性放射性核素的全身方法，这为将免疫调节辐射传递到转移性肿瘤部位提供了另一种选择，而无需威斯康星大学麦迪逊分校的 Weichert 实验室开发了一种新型药物。 TRT 类，称为 NM600，是一种烷基磷酸胆碱类似物，可选择性地吸收并保留在近乎我们的广泛假设是放射性核素的独特物理特性（例如，发射类型、线性能量转移、半衰期、组织范围）对 TRT 的免疫调节有不同的影响。本研究将发射α-(225Ac)和β-(90Y)粒子放射性核素的免疫调节能力在一个建立在 Morris 和 Weichert 持续合作进展基础上的项目中进行了直接比较。实验室，我们现在将确定 TRT 与免疫疗法相结合的放射性核素特异性效力，以增强在小鼠模型中，我们将：1）扩展初步的免疫反应。数据显示 TRT 和 ICI 组合具有有效的协同作用，2）评估 TRT 的治疗机制和 ICI，利用 225Ac- 和 90Y-NM600 的内在特性，重点关注 I 型 IFN 反应激活和 3) 研究两种不同放射性核素与 ICI 组合的潜在增强肿瘤反应。这些研究中开发的见解和治疗方案应该能够快速转化为临床测试患者和潜在的任何类型的转移性癌症。