Early response to radiotherapy and immunotherapy in rectal cancer: an integrated molecular, cellular, and spatial approach

项目摘要 随着年轻人群发病率的增加和高危局部晚期复发性乳腺癌的约65%的3年生存率， 谈到癌症，改善治疗结果创新方法势在必行。新辅助放疗（RT） 化疗（CT）现在是标准的治愈性治疗，但需要非手术治疗， 如果疾病可以通过局部和全身治疗治愈，则为NOM。因此，创新可能是跨性别的， 形成性，旨在通过个性化治疗改善持久的完全反应，其中包括如何 提供RT、CT和掺入新的药物，如免疫疗法。癌症免疫治疗 对错配修复缺陷肿瘤以外的结直肠癌几乎没有影响。α CD 40激动剂抗体 是一种新兴的免疫疗法，sotigalimab已在I期和多个正在进行的研究中显示出前景。 第二阶段试验。CD 40受体在先天性和适应性免疫应答中都很重要， 在动物模型中α CD 40与RT联合应用可达到治疗效果。我们假设， 在人类肿瘤中，疗程RT（SCRT）和CT与α CD 40联合使用可产生更大的抗肿瘤作用。 免疫应答，降低转移进展的风险，延长免疫原性差的恶性肿瘤的生存期， 类似直肠癌。我们开发了INNATE试验，这是一项新辅助SCRT的II期随机试验， 局部进展期直肠癌的CT（加或不加sotigalimab）降低。该试验设计具有 使我们能够收集新鲜的SCRT前后活检组织，我们从30名患者中的21名获得 注册至今。在这个建议中，我们集中在一个中心假设，即一个整合的分子，细胞， SCRT后早期肿瘤微环境中治疗反应动力学的空间评估可以重新评估 对免疫生物学反应的深入了解，可以为疗效和治疗机制提供信息。 选择.我们将进行1）分子和细胞单细胞（sc）RNAseq与蛋白质组学和免疫反应， 汇辑分析，2）分子、细胞和空间多重免疫荧光，和3）细胞和空间 基于定量深度学习的组织病理学分析，以实现我们的目标。这三项技术将 使我们能够研究RT和α CD 40治疗组的早期变化。我们要找出- SCRT与免疫活性剂联合应用的可能性， sponse评估最后，我们将建立先天性和适应性免疫信号事件触发的 SCRT联合α CD 40免疫治疗以及增强或阻碍疗效的因素。我们将使用 模型开始验证关键发现，并旨在提出未来的治疗方向，以建立这些努力 并最终改善结果。具体而言，就我们的患者群体而言，我们预计这项提案将 导致对大多数努力实现治愈的局部晚期直肠癌患者进行基于证据的试验 不做手术的话

Project Abstract With increased incidence in young populations and ~65% three-year survival of high-risk locally advanced rec- tal cancer, innovative approaches to improve outcomes is imperative. Neoadjuvant therapy with radiation (RT) and chemotherapy (CT) is now the standard curative treatment, but there is demand for non-operative man- agement (NOM) if the disease can be cured with local and systemic therapy. Thus, innovations could be trans- formative with the aim to improve durable complete responses by personalizing therapy, which includes how to deliver RT, CT, and the incorporation of novel agents such as immunotherapy. Cancer Immunotherapy has had little impact on colorectal cancer outside of mismatch repair deficient tumors. The αCD40 agonist antibody is an emerging class of immunotherapy and sotigalimab has shown promise in phase I and multiple ongoing phase II trials. The CD40 receptor is important in both innate and adaptive immune responses and a greater therapeutic effect can be achieved combining αCD40 with RT in animal models. We hypothesize that short course RT (SCRT) and CT when combined with αCD40 in human tumors can result in a greater antitumor im- mune response, reduce risk of metastatic progression, and extend survival in a poorly immunogenic malig- nancy like rectal cancer. We developed the INNATE trial, a phase II randomized trial of neoadjuvant SCRT fol- lowed by CT with or without the addition of sotigalimab for locally advanced rectal cancer. This trial design has allowed us to collect fresh pre- and post-SCRT biopsy tissue, which we have obtained from 21 of 30 patients enrolled to date. In this proposal, we focus on the central hypothesis that an integrated molecular, cellular, and spatial assessment of treatment response dynamics in the tumor microenvironment early after SCRT can re- veal insights into the immunobiological responses, which can inform mechanisms of efficacy and therapeutic selection. We will perform 1) molecular and cellular single cell (sc) RNAseq with proteomic and immune reper- toire analysis, 2) molecular, cellular, and spatial multiplex immunofluorescence, and 3) cellular and spatial quantitative deep learning based histopathologic analysis to achieve our aims. These three technologies will enable us to investigate early changes across RT and αCD40 treated groups. Then we will aim to identify ther- apeutic opportunities for the combination of SCRT with immune active agents though an integrated RT re- sponse assessment. Lastly, we will establish innate and adaptive immunologic signaling events triggered by SCRT in combination with αCD40 immunotherapy and factors that enhance or hinder efficacy. We will use models to start validating key findings and aim to propose future therapeutic directions to build off these efforts and ultimately improve outcomes. Specifically, regarding our patient population, we expect this proposal will lead to evidenced based trials for most patients with locally advanced rectal cancer who strive to achieve cure without a morbid surgery.