Finding Sleeping Beauty: T Cell Biosensors for Dormant Cancer Detection

寻找睡美人：用于检测休眠癌症的 T 细胞生物传感器

• 批准号: 10707371
• 负责人: Gabriel A Kwong
• 金额: $ 110.74万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707371
• 关键词: Antibodies; Antigens; Binding; Biological Markers; Biosensor; Blood; Bone Marrow; Breast Cancer Patient; Cancer Detection; Cells; Clinical; Detection; Disease; Engineering; Estrogen receptor positive; Future; Genetic; Growth; Image; In complete remission; Libraries; Life; Lung; Malignant Neoplasms; Medicine; Memory; Meta-Analysis; Methods; Micrometastasis; Monitor; No Evidence of Disease; Patients; Peptide Hydrolases; Peptides; Phenotype; Proteolysis; Recurrence; Relapse; Relative Risks; Reporting; Risk; Sensitivity and Specificity; Site; Sleeping Beauty; Symptoms; T cell therapy; T-Cell Activation; T-Lymphocyte; Technology; Therapeutic Intervention; Tumor Antigens; Urine; angiogenesis; cancer immunotherapy; cancer type; design; engineered T cells; extracellular; hormone therapy; in vivo; malignant breast neoplasm; neoplastic cell; receptor; screening; sensor; treatment response; tumor

PROJECT SUMMARY Some types of cancers, as exemplified by estrogen receptor positive breast cancer, can recur as metastatic disease many years or even decades following a dormancy period where the patient displays no clinical symptoms. Late recurrence is thought to arise from disseminated tumor cells (DTCs) that were not killed by initial treatment and that lie dormant at metastatic sites such as the bone marrow until they reawaken. Strikingly, meta- analysis of over 60,000 early-stage ER-positive breast cancer patients treated with endocrine therapy revealed that the relative risk of recurrence progressively increases over a period of at least 20 years, indicating that patients in complete remission with no evidence of disease could harbor dormant cancer and remain at risk of metastatic relapse for the remainder of their life. Currently, there is no widely used method to monitor the dormant state nor its reawakening. The arrival of cancer immunotherapy has revealed exciting possibilities using engineered T cells as living medicines. T cells designed with tumor-targeting receptors and sophisticated genetic circuits have led to striking treatment responses in patients with certain types of cancers that were previously untreatable. This moment is an opportunity to not only build a future where T cells are engineered as therapies, but also as living sensors that can detect cancer with sensitivities and specificities beyond what is currently possible. The activation and growth of dormant tumor cells into micro-metastases require the hallmark expression of proteases during key steps such as angiogenesis. To exploit protease dysregulation, this project will develop engineered receptors that sense proteolysis to detect reawakening. These contain an extracellular single chain antibody that is blocked by a peptide mimotope such that they can bind to their cognate antigens only after the blocking peptide is removed by proteolysis, restricting T cell activation to the specific condition where the cognate protease and tumor antigen are both present. Following activation, T cell sensors amplify the release of synthetic biomarkers (blood, urine and imaging) for detection. Genetically encoded libraries (>10^4) of protease-activatable receptors will allow in vivo screening of 1000s of candidate T cell sensors to positively and negatively select for constructs that can report on awakening in different microenvironments such as the bone marrow and lungs. The adoptive transfer of T cell sensors with memory phenotype could lead to life-long T cell sensors that continuously monitor for future disease. These technological breakthroughs will have huge implications in understanding how and when dormant cells reawaken and guide therapeutic interventions at the earliest stages of reactivation.

项目摘要 雌激素受体阳性乳腺癌所举例说明的某些类型的癌症可以复发为转移性 在休眠期内，患者没有临床的时间多年甚至几十年 症状。人们认为晚期复发是由散布的肿瘤细胞（DTC）引起的 治疗并在骨髓等转移部位处于休眠状态，直到它们复活为止。令人惊讶的是，meta- 分析接受内分泌治疗治疗的60,000多个早期ER阳性乳腺癌患者 在至少20年的时间内，复发的相对风险逐渐增加，表明 完全缓解的患者没有任何疾病的证据可能怀有休眠的癌症，并仍处于 余生的转移性复发。当前，没有广泛使用的方法来监测休眠状态 状态和唤醒。癌症免疫疗法的到来揭示了使用 设计T细胞为活药物。 T细胞由靶向肿瘤的受体和复杂的遗传设计 电路导致了某些类型的癌症患者的惊人治疗反应 无法治疗。这一刻不仅是建立T细胞作为疗法设计的未来的机会， 但作为可以检测具有敏感性和特异性癌症的生物传感器 可能的。休眠肿瘤细胞进入微焦点酶的激活和生长需要标志 在血管生成等关键步骤中的蛋白酶的表达。为了利用蛋白酶失调，该项目 将开发工程的受体，可以感觉到蛋白水解检测重新唤醒。这些包含细胞外 单链抗体被肽模拟物阻断，使它们可以与同类抗原结合 仅在通过蛋白水解去除阻塞肽后，将T细胞激活限制为特定条件 同源蛋白酶和肿瘤抗原都存在。激活后，T细胞传感器扩大了 释放合成生物标志物（血液，尿液和成像）进行检测。基因编码的库（> 10^4） 蛋白酶 - 可激活的受体将允许1000候选T细胞传感器的体内筛选积极 并负面选择可以报告不同微环境中觉醒的结构，例如 骨髓和肺。具有记忆表型的T细胞传感器的收养转移可能导致终身 T细胞传感器不断监测未来疾病。这些技术突破将具有巨大的 了解休眠细胞如何以及何时重新恢复和引导治疗干预措施的含义 重新激活的最早阶段。