Tissue engineering tools for monitoring the cellular and molecular response to therapy

概述：三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌， 靶向原发性肿瘤和全身性疾病的新辅助治疗， 免疫疗法即使使用最先进的治疗方法，大约20%的患者， 尽管有病理完全缓解（pCR），但仍存在局部或远端组织残留疾病， 可能导致局部或远端组织内的疾病复发。我们发明了一种新技术- 用作合成转移小生境（MN）的支架-其捕获全身效应（即，免疫 变化，肿瘤细胞），并可用于监测疾病负荷，进展，或 回归分析支架的孔隙允许宿主细胞浸润和血管向内生长， 基于异物反应被植入物吸引。在一只荷瘤小鼠中， 与无肿瘤小鼠不同，反映了在内源性组织中观察到的变化（即， 肺），因为癌症开始和进展后的全身性变化。这些浸润的免疫细胞 在肿瘤细胞到达之前，准备好定植部位，并促进疾病进展。我们 提出该支架可用于新辅助和辅助治疗后疾病的纵向监测， 免疫疗法疾病监测基于支架内的分子和细胞组成（例如， 免疫细胞或肿瘤细胞），其反映了残留疾病的系统性影响。提案的目的 包括：目标1将开发一种预后标志，可以确定对新辅助治疗的反应， 反映残留疾病的存在。支架将补充原发部位的组织学分析 并且可以通过对细胞和分子的系统性影响来指示残留疾病的存在 支架中的表型。支架分析将与患者组织的组织学进行比较，目标是 识别pCR不能捕获残留疾病的情况。在目标2中，我们建议调查 使用支架监测复发和监测辅助治疗期间的反应。我们还将 分析支架对免疫检查点产生抗性的机制 阻断（ICB）。残留疾病的识别通常发生在患者自我报告症状时， 晚期疾病复发。我们的平台通过预先定义要分析的位置克服了这一关键障碍 疾病的系统性影响。总的来说，这些支架在体内提供了一个确定的位点来分析， 捕获残留疾病对远端组织的全身影响。像肺这样的实体器官， 由于手术的发病率和早期转移灶较小， 并且难以在整个器官内检测到。总的来说，支架提供了一种监测残留物的工具。 新辅助治疗或辅助治疗后的疾病，风险最小，细胞和 分子分析指导个体化治疗，有可能提高生存率并降低成本。

Summary: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is treated with neoadjuvant therapy that targets both the primary tumor and systemic disease, with subsequent adjuvant immunotherapy. Even with the most cutting-edge therapeutic approach, approximately 20% of these patients, despite a pathologic complete response (pCR), have residual disease, present locally or in distal tissues, which may lead to disease recurrence either locally or within distal tissues. We have devised a novel technology – a scaffold that serves as a synthetic metastatic niche (MN) – that captures the systemic effects (i.e., immunological changes, tumor cells) of residual disease and could be employed to monitor for disease burden, progression, or regression. The pores of the scaffold allow for host cell infiltration and vascular ingrowth, with immune cells attracted to the implant based on a foreign body response. In a tumor-bearing mouse, the immune cells recruited to the implant are distinct from tumor-free mice, reflecting the changes observed in endogenous tissues (i.e., lung) because of systemic changes following cancer initiation and progression. These infiltrating immune cells precede the arrival of tumor cells, prepare the site for colonization, and facilitate disease progression. We propose that the scaffold can be used for longitudinal monitoring of disease following neoadjuvant and adjuvant immunotherapy. Disease monitoring is based on the molecular and cellular composition within the scaffold (e.g., immune cells or tumor cells) that reflect the systemic impacts of residual disease. The aims of the proposal include: Aim 1 will develop a prognostic signature that can determine response to neoadjuvant therapy and reflect the presence of residual disease. The scaffold will supplement the histological analysis of the primary site and can indicate the presence of residual disease through the systemic effects on cellular and molecular phenotypes in the scaffold. The scaffold analyses will be compared with histology of patient tissue, with the goal of identifying situations in which a pCR does not capture residual disease. In Aim 2, we propose to investigate the use of scaffolds for surveillance of recurrence and monitoring response during adjuvant therapy. We will also analyze the scaffold for the mechanisms that underlie the development of resistance to immune checkpoint blockade (ICB). Identification of residual disease typically occurs when patients self-report symptoms, indicating late-stage disease recurrence. Our platform overcomes this critical barrier by pre-defining a location to analyze for the systemic effects of disease. Collectively, these scaffolds provide a defined site in vivo to analyze that captures the systemic effects of residual disease on distant tissues. A solid organ, such as lung, cannot be readily monitored over time in a patient due to the morbidity of the procedure and early metastatic foci are small and difficult to detect within the total organ. Collectively, the scaffolds provide a tool to monitor for residual disease following neo-adjuvant or adjuvant therapy that is accessible with minimal risk, with the cellular and molecular analyses guiding individualized treatments with the potential to improve survival and reduce costs.