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

在过去的三年里，继FDA之后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一些适应症，包括转移性黑色素瘤 和非小细胞肺癌。这些新的代理人通过有效地释放刹车 免疫系统，通常限制身体对肿瘤细胞的自然反应，并已产生 然而，长期缓解，甚至是一些治疗方法，其发展、应用和潜力 这些新疗法受阻于相对较低的应答率和所需的较长时间 确定客观的反应。免疫疗法费用昂贵，而且有严重的潜在副作用 因此，及早为每个患者选择最有效的治疗方法是至关重要的。目前，没有 测量反应的有效方法，如活组织检查和解剖成像等传统方法 没有预见性。为了克服这些限制，我们开发了一种分子显像剂，用于 正电子发射断层扫描(PET)靶向颗粒酶B，激活后释放的酶 免疫细胞杀死靶肿瘤细胞。通过非侵入性测量肿瘤细胞的浓度 颗粒酶B，我们已经展示了我们的PET显像剂预测早期的特异性和潜力 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 体外肿瘤组织特异性分析证明我们的靶点显示颗粒酶B水平 可以预测黑色素瘤患者样本的反应。鉴于我们的代理已取得初步成功 确定免疫治疗的反应和缺乏有效的替代方案，我们认为加速 翻译成人体测试是有必要的。这份SBIR建议书包括准备和完成 一项探索性-IND研究，以证明在一小群黑色素瘤患者中的安全性，并 确定接受检查点抑制剂治疗的人体的安全性、分布和成像潜力 心理治疗。尽管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黄金标准 应答者与非应答者。

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.