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视网膜病变的三年存活率约65%。 对于TAL癌症，创新的方法来改善结果是势在必行的。新辅助放射治疗(RT) 化疗(CT)现在是标准的治疗方法，但对非手术治疗的需求也很大。 治疗(NOM)如果疾病可以通过局部和系统治疗治愈。因此，创新可以是跨越式的 形成，目的是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和免疫治疗等新药物的整合。癌症免疫疗法已经 除错配修复缺陷肿瘤外，对结直肠癌的影响不大。αCD40激动型抗体 是一种新兴的免疫疗法，Sotigalimab在I期和多个正在进行的 第二阶段试验。CD40受体在先天性免疫反应和获得性免疫反应中都很重要，而且更重要的是 在动物模型中，αCD40联合RT可达到治疗效果。我们假设短时间内 α-CD_(40)联合放射治疗和CT治疗人肿瘤可产生较强的抗肿瘤免疫作用 免疫应答，降低转移进展的风险，并延长免疫原性低的恶性肿瘤的生存时间。 南希喜欢直肠癌。我们开发了先天试验，这是一项新辅助SCRT的II期随机试验。 局部进展期直肠癌加用或不加用Sotigalimab均可通过CT降低。这一试验设计具有 使我们能够收集新鲜的SCRT前后的活检组织，我们从30名患者中的21名获得 到目前为止已经注册。在这个提议中，我们关注的中心假设是，一个完整的分子、细胞和 SCRT后早期肿瘤微环境中治疗反应动力学的空间评估可以恢复 小牛肉对免疫生物学反应的洞察，这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蛋白质组和免疫反应- TOIRE分析，2)分子、细胞和空间多重免疫荧光，以及3)细胞和空间 基于定量深度学习的组织病理学分析，以达到我们的目标。这三项技术将 使我们能够调查RT和αCD40处理组的早期变化。然后我们将致力于确定他们- SCRT与免疫活性药物结合的综合RT治疗机会 自助式评估。最后，我们将建立先天和获得性免疫信号事件，由 SCRT联合α、CD40免疫治疗及增强或阻碍疗效的因素。我们将使用 开始验证关键发现的模型，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。具体地说，对于我们的患者群体，我们预计这项提案将 为大多数力争治愈的局部晚期直肠癌患者进行循证试验 不用做病态的手术。

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.