Spatially precise radio-chemo-immunotherapy using antibody conjugates

使用抗体偶联物进行空间精确的放射化学免疫治疗

基本信息

批准号：
10585803
负责人：
Sunil J Advani
金额：
$ 53.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585803
关键词：
Antibodies Antibody-drug conjugates Binding CD8-Positive T-Lymphocytes Cancer Model Cancer Patient Carcinogens Cell Surface Receptors Cell membrane Cells Cetuximab Clinical Coupled Cytotoxic Chemotherapy Cytotoxic agent Cytotoxin DNA Damage DNA Repair Data Dose Limiting ERBB2 gene Epidermal Growth Factor Receptor Goals Grant Immune Immune checkpoint inhibitor Immune response Immuno-Chemotherapy Immunocompetent Immunotherapy Implant Ionizing radiation Irradiated tumor Link Locally Advanced Malignant Neoplasm Modeling Molecular Morbidity - disease rate Mus Normal tissue morphology Organ Pathway interactions Patients Pharmaceutical Preparations Quality of life Radiation induced damage Radiation therapy Radiation-Sensitizing Agents Radio Radiosensitization Role Schedule Systemic Therapy Techniques Technology Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Trastuzumab Treatment-related toxicity Tubulin adaptive immune response anti-tumor immune response antibody conjugate carcinogenesis checkpoint inhibition chemoradiation chemotherapy clinically relevant curative treatments cytotoxic cytotoxicity delivery vehicle design drug development efficacy testing immune cell infiltrate immunogenic improved improved outcome inhibitor innovation interest mouse model neoplastic cell novel therapeutics pre-clinical precision medicine programmed cell death protein 1 receptor receptor binding response success systemic toxicity targeted delivery tool tumor tumor specificity tumor xenograft tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Locally advanced cancers remain a therapeutic challenge to eradicate. The most successful treatments for such patients continue to combine decades old classical cytotoxic chemotherapies with radiotherapy. While chemo-radiotherapy improves tumor control, using non-targeted drugs increases normal tissue damage in the irradiated field along with systemic toxicities precluding further treatment intensification. Targeted delivery approaches can improve the chemo-radiotherapy paradigm by restricting highly potent radiosensitizers specifically to irradiated tumor targets that activate anti-tumor immune responses while simultaneously avoiding normal tissues. To test this hypothesis, we leveraged antibody drug conjugate (ADC) technology for receptor-restricted radiosensitization. ADCs split the roles of tumor targeting and killing into two distinct molecular tasks. Targeting is achieved by the antibody portion recognizing cell surface receptors preferentially found on tumor cells. Following cell surface receptor binding, ADCs are endocytosed and the attached drug payload warhead intracellularly released specifically within target cells. ADCs have been exclusively built by linking cytotoxic drugs to tumor targeting antibodies. The potent anti-tubulin drug monomethyl auristatin E (MMAE) is the most common ADC warhead. We discovered MMAE could also radiosensitize. Advancing to syngeneic murine models using our novel drug delivery vehicles, we have now provided the first demonstration that MMAE produces durable irradiated tumor control which is dependent on CD8 T cells and is enhanced by immune checkpoint inhibition. While antibody coupled, MMAE is target restricted. However once released, MMAE has dose limiting toxicities. To achieve increasingly precise tumor radiosensitization, we used orthogonal strategies and rationally constructed a first-in-class radiosensitizing ADC designed to inhibit DNA damage repair. As proof of concept, we conjugated anti-EGFR antibody cetuximab to ATM inhibitor AZD0156 (cetux-AZD0156). Cetux-AZD0156 specifically bound and delivered drug to EGFR+ tumors while avoiding adjacent peri-tumoral normal tissue. Moreover, cetux-AZD0156 radiosensitized and increased irradiated tumor control. Based on these findings, we hypothesize that anti-ErbB ADCs coupled to radiosensitizing warheads improve spatial precision of radiosensitization and engage the tumor immune microenvironment (TIME). The goals of this proposal are to methodically test this hypothesis by evaluating radiosensitizing ADC warheads in murine tumor models using our innovative toolbox of tumor-targeted radiosensitizing ADC warheads. In Aim 1, we will test the ability of auristatins to sculpt the irradiated TIME and promote immunogenic tumor control. In Aim 2, we will test if immunotherapies potentiate radiosensitizing auristatins to achieve durable tumor control. In Aim 3, we will test first-in-class ADCs with ATM inhibitor warheads for tissue selective radiosensitization. Rigorously testing radiosensitizing ADCs in advanced murine models will provide rationale for moving away from non-targeted chemo-radiotherapy toward molecularly guided precision radio-chemo-immunotherapies.

项目摘要/摘要当地高级癌症仍然是消除的治疗挑战。最成功的治疗方法这样的患者继续将数十年的古典细胞毒性化学疗法与放射疗法结合在一起。尽管化学放射治疗改善了使用非靶向药物的肿瘤控制，从而增加了正常的组织损伤辐照场以及全身毒性排除了进一步的治疗强化。目标交付方法可以通过限制高度有效的放射增敏剂来改善化学放射治疗范式专门针对激活抗肿瘤免疫反应的辐照肿瘤靶标避免正常组织。为了检验这一假设，我们利用抗体药物缀合物（ADC）技术受体限制的放射敏化。 ADC将肿瘤靶向和杀死的作用分为两个不同分子任务。靶向是通过优先识别细胞表面受体的抗体部分实现的在肿瘤细胞上发现。遵循细胞表面受体结合，ADC被内吞和附着的药物有效载弹头细胞内专门在目标细胞内释放。 ADC是由将细胞毒性药物与靶向抗体的肿瘤联系起来。有效的抗微管蛋白药物单甲基甲氨酸蛋白E （MMAE）是最常见的ADC弹头。我们发现MMAE也可以放射敏感。前进合成鼠模型使用我们的新型药物，我们现在提供了第一个演示 MMAE产生持久的辐照肿瘤控制，该控制取决于CD8 T细胞，并通过免疫检查点抑制。抗体耦合时，MMAE受到靶向限制。但是一旦发布， MMAE具有限制毒性的剂量。为了实现越来越精确的肿瘤放射敏化，我们使用了正交策略和合理构建了旨在抑制DNA的第一类放射性ADC 损坏维修。作为概念证明，我们将抗EGFR抗体西妥昔单抗与ATM抑制剂AZD0156结合（cetux-azd0156）。 CETUX-AZD0156在避免的同时，专门将药物与EGFR+肿瘤交付邻近肿瘤周期正常组织。此外，CETUX-AZD0156放射敏化并增加了辐照的肿瘤控制。基于这些发现，我们假设抗erbb ADC与放射性敏锐的弹头耦合提高放射敏化的空间精度并参与肿瘤免疫微环境（时间）。这该提案的目标是通过评估放射敏感的ADC弹头来有条不紊地检验该假设使用我们创新的肿瘤靶向放射敏感ADC弹头的鼠肿瘤模型。在AIM 1中，我们将测试极光素雕刻辐照时间并促进免疫原性肿瘤控制的能力。在 AIM 2，我们将测试免疫疗法是否会增强放射敏感性的auristatins以实现耐用的肿瘤控制。在AIM 3中，我们将使用ATM抑制剂弹头测试一流的ADC，以进行组织选择性放射敏化。严格测试高级鼠模型中的放射敏化ADC将为搬离提供理由从非靶向化学疗法到分子指导的精确放射性化理免疫疗法。