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

在过去的三年里，一个全新的癌症治疗模式已经出现， 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。这些新的代理人的工作，有效地释放刹车的 免疫系统通常限制身体对肿瘤细胞的自然反应， 长期缓解，甚至一些治愈，但是，开发，应用和潜力， 这些新的治疗方法受到相对较低的反应率和所需时间的阻碍， 确定客观答案。免疫疗法是昂贵的，并带有严重的潜在的一面 因此，尽早为每位患者选择最有效的治疗方法至关重要。目前尚无 有效的方法来衡量反应，因为传统的方法，如活检和解剖成像， 没有预测。为了克服这些局限性，我们开发了一种分子成像剂， 正电子发射断层扫描（PET）靶向颗粒酶B，该酶由活化的 免疫细胞杀死目标肿瘤细胞。通过非侵入性地测量肿瘤中 颗粒酶B，我们已经显示了我们的PET显像剂的特异性和潜力，以预测早期 用体内非临床癌症模型对检查点抑制剂的反应。我们已经扩大了我们的工作 在人癌组织中的离体特异性分析以证明我们的靶显示颗粒酶B水平 可以预测黑素瘤患者样品中的反应。鉴于我们的探员初步成功地 确定免疫治疗反应和缺乏有效的替代品，我们认为， 翻译成人类测试是有保证的。该SBIR提案包括准备和完成 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， 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 疗法虽然这项研究不能确定疗效，但PET成像数据将被用于 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 应答者vs无应答者。

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.