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Clinical Translation of a Novel Diagnostic Agent to Predict Immunotherapy Response in Solid Tumors

预测实体瘤免疫治疗反应的新型诊断剂的临床转化

基本信息

批准号：
10017924
负责人：
JAMES F KRONAUGE
金额：
$ 77.47万
依托单位：
CYTOSITE BIOPHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017924
关键词：
Acute Toxicity Tests Apoptosis Biopsy Cancer Model Cancer Patient Case Report Form Cell Death Cells Chelating Agents Chemistry Clinical Clinical Protocols Clinical Research Coenzyme A Complex Contracts Cytoplasmic Granules Data Detection Development Disease remission Dose Enrollment Enzymes Formulation Gallium General Hospitals Goals Gold Granzyme High Pressure Liquid Chromatography Human Image Immune Immune checkpoint inhibitor Immune system Immunooncology Immunotherapy In Vitro Injections Institutional Review Boards Label Lymphocyte Lymphocyte Activation Magnetic Resonance Imaging Malignant Neoplasms Massachusetts Measures Mediating Metastatic Melanoma Methods Michigan Modeling Monitor New Agents Non-Small-Cell Lung Carcinoma Patient imaging Patients Peptides Pharmaceutical Preparations Phase Physicians Physiological Positron-Emission Tomography Preclinical Testing Preparation Process Production Proteins Radiolabeled Radiometry Radiopharmaceuticals Rattus Records Reference Standards Reporting Rodent Safety Sampling Serine Protease Services Site Small Business Innovation Research Grant Solid Neoplasm Specificity Technology Testing Time TimeLine Tissues Toxicity Tests Translating Translations Validation Visualization Work acute toxicity analytical method anatomic imaging cancer therapy checkpoint therapy clinical translation cytotoxic effective therapy empowered extracellular follow-up imaging agent imaging potential imaging study immune activation in vivo intravenous injection melanoma molecular imaging neoplastic cell novel diagnostics peptide drug pre-clinical preclinical imaging predicting response research clinical testing responders and non-responders response scale up side effect stability testing sterility testing success translation to humans tumor tumor microenvironment

项目摘要

Over the past three years an entirely new cancer treatment paradigm has emerged following the FDA approval of 6 different checkpoint inhibitors for a number of indications including; metastatic melanoma and non-small cell lung cancer. These new agents work by effectively releasing the brakes on the immune system that normally limit the body’s natural responses to tumor cells and have generated long-term remission, and even some cures, However, the development, application and potential of these new treatments is hindered by relatively low response rates and the long-times required to ascertain objective responses. Immunotherapy is expensive and comes with serious potential side effects, so early selection of the most effective therapy for each patient is critical. Currently, there is no effective way to measure response, as traditional methods such as biopsy and anatomic imaging have not been predictive. To overcome these limitations, we have developed a molecular imaging agent for Positron Emission Tomography (PET) that is targeted to granzyme B, the enzyme released by activated immune cells to kill target tumor cells. By non-invasively measuring the tumor concentration of granzyme B, we have shown the specificity and potential of our PET imaging agent to predict early response to checkpoint inhibitors with in vivo non-clinical cancer models. We have extended our work ex vivo specificity analysis in human cancer tissue to demonstrate our target shows granzyme B levels are predictive of response in melanoma patient samples. Given the preliminary success of our agent to determine immunotherapy response and the lack of effective alternatives, we believe an accelerated translation to human testing is warranted. This SBIR proposal includes the preparation and completion of an exploratory-IND study to demonstrate safety in a small group of Melanoma patients and to determine safety, distribution and imaging potential in humans undergoing checkpoint inhibitor therapy. Although, this study cannot be empowered to determine efficacy, PET imaging data will be correlated with clinical follow up and melanoma biopsy data as a gold-standard for Immuno-Oncology responders vs non-responders.

在过去的三年里，随着 FDA 的批准，出现了一种全新的癌症治疗模式批准 6 种不同的检查点抑制剂用于多种适应症，包括：转移性黑色素瘤和非小细胞肺癌。这些新代理的工作原理是有效地释放对免疫系统通常会限制人体对肿瘤细胞的自然反应，并产生长期缓解，甚至部分治愈，但其开发、应用及潜力这些新疗法因反应率相对较低且需要较长时间而受到阻碍确定客观反应。免疫疗法价格昂贵且具有巨大的潜力因此，尽早为每位患者选择最有效的治疗方法至关重要。目前，没有测量反应的有效方法，如活检和解剖成像等传统方法没有被预测到。为了克服这些限制，我们开发了一种分子成像剂正电子发射断层扫描 (PET) 以颗粒酶 B 为目标，颗粒酶 B 是一种被激活的酶释放的酶。免疫细胞杀死目标肿瘤细胞。通过非侵入性测量肿瘤浓度颗粒酶 B，我们已经展示了我们的 PET 显像剂在早期预测方面的特异性和潜力体内非临床癌症模型对检查点抑制剂的反应。我们已经延长了我们的工作对人类癌症组织进行离体特异性分析，以证明我们的目标显示颗粒酶 B 水平可以预测黑色素瘤患者样本中的反应。鉴于我们的代理取得了初步成功确定免疫疗法的反应和缺乏有效的替代方案，我们相信加速转化为人体测试是有必要的。本 SBIR 提案包括准备和完成一项探索性 IND 研究旨在证明一小群黑色素瘤患者的安全性并确定接受检查点抑制剂的人类的安全性、分布和成像潜力治疗。虽然这项研究不能确定疗效，但 PET 成像数据将与临床随访和黑色素瘤活检数据相关，作为免疫肿瘤学的金标准响应者与非响应者。