Nanoscale Coordination Polymers of Cyclic-di-nucleotides and Peptide Antigens for Effective Therapy of Metastatic Colorectal Cancer

项目摘要：新方法，例如过去出现的免疫检查点封锁 十年，为转移性癌症患者带来了巨大的希望。事实上，PD-1/PD-L1封锁已经享有 免疫原性“热点”肿瘤，如黑色素瘤亚群和非小细胞肿瘤的显著临床成功 肺癌患者；但对于免疫“冷”的肿瘤患者，如最晚期 对于结直肠癌，患者的应答率可低至5%。随着全基因组测序的到来 和先进的生物信息学技术，肿瘤中的患者特异性新抗原现在可以被识别和 为临床前和临床开发中的许多治疗性疫苗提供基础。基于新抗原的 癌症疫苗可以通过识别他们独特的新抗原来为个别患者量身定做。 我们率先开发了纳米配位聚合物(NCP)，这是一类 由金属离子和多齿桥联配体自组装而成的杂化纳米颗粒。NCP 利用增强的渗透性和保留性在肿瘤组织中优先蓄积 与现有的纳米载体相比，它具有多种优势。我们协作的长期目标是 研究是为了建立转移性结直肠癌的治疗新范式，通过开发 以及能够有系统地交付的有效NCP的特征。 拟议研究的总体目标是为系统开发健壮的NCP，即ZCDN 递送新抗原和亲水性环二核苷酸(CDN)刺激剂，包括CDA，Adu-S100， 而MK-1454对增强抗肿瘤免疫效果的抗PD-L1免疫治疗有效 多发性结直肠癌的治疗。增加对这种联合疗法所涉及的机制的了解将 为提高多发性结直肠癌免疫疗法的应答率和耐受性提供重要见解。 我们设计了以CDA和Zn2+离子为核，PEG2000为亲水性外壳的ZnCDN NCP 抵抗单核细胞吞噬系统对血浆蛋白质的吸收和清除。因此，ZnCDN可以 给小鼠静脉注射可在TME内显著蓄积。我们将研究三个方面 用CDA、ADU-S100和MK-1454配制锌镉氮，以获得最佳的锌镉氮，并评价其对 肿瘤血管和肿瘤内滞留。我们将评估mCRC小鼠模型的免疫激活情况， 阐明了肿瘤微环境中ZnCDN介导的STING激活机制。按顺序 为了评估肿瘤特异性抗原的传递，我们将肿瘤抗原肽引入NCPs中，以 促进CD8+T细胞的交叉激发，增强抗肿瘤效果。最后，我们将阐明 ZCDN抗原激活STING克服PD-1/PD-L1阻断抗性的机制 多年来，我们的实验室一直在路德维希转移研究中心共同开展这一项目 在过去十年里。这种跨学科的努力可能会导致对多发性结直肠癌治疗的转变。

Project Summary: New approaches, such as the emergence of immune checkpoint blockade over the past decade, hold great promise for patients with metastatic cancer. Indeed, PD-1/PD-L1 blockade has enjoyed remarkable clinical success for immunogenically “hot” tumors such as subsets of melanoma and non-small cell lung cancer patients; however, for patients with immunologically “cold” tumors, such as most advanced colorectal cancers, patient response rates can be as low as 5%. With the advent of whole genome sequencing and sophisticated bioinformatics techniques, patient-specific neoantigens in tumors can now be identified and provide the basis for many therapeutic vaccines in preclinical and clinical development. Neoantigen-based cancer vaccines can be tailored to individual patients by identifying their unique neoantigens. We have pioneered the development of nanoscale coordination polymers (NCPs), which are a class of hybrid nanoparticles formed by the self-assembly of metal ions and polydentate bridging ligands. NCPs preferentially accumulate in tumor tissues by taking advantage of the enhanced permeability and retention effect and possess several advantages over existing nanocarriers. The long-term goal of our collaborative research is to establish a new treatment paradigm for metastatic colorectal cancer, through the development and characterization of effective NCPs that can be delivered systemically. The overall goal of the proposed studies is to develop robust NCPs, namely, ZnCDN, for the systemic delivery of a neoantigen and hydrophilic cyclic dinucleotide (CDN) STING agonists, including CDA, ADU-S100, and MK-1454, to potentiate the antitumor immune effect of anti-PD-L1 immunotherapy for the effective treatment of mCRC. Increased understanding of the mechanisms involved in this combination therapy will provide critical insights to enhance the response rates and durability of immunotherapies for mCRC. We have designed ZnCDN NCP with a core of CDA and Zn2+ ions and a hydrophilic shell of PEG2000 to resist plasma protein absorption and clearance by the monocytic phagocytic system. As a result, ZnCDN can be administered to mice via intravenous injection to significantly accumulate in the TME. We will study three ZnCDN formulations with CDA, ADU-S100, and MK-1454 to obtain the best ZnCDN and evaluate its effects on tumor vasculature and intratumoal retention. We will evaluate immune activation in mouse models of mCRC, and elucidate the mechanisms of ZnCDN-mediated STING activation in the tumor microenvironment. In order to evaluate the delivery of tumor-specific antigens, we will incorporate tumor antigen peptides into NCPs to facilitate cross-priming of CD8+ T cells and enhance antitumor efficacy. Finally, we will elucidate the mechanism of STING activation with ZnCDN-antigen to overcome resistance to PD-1/PD-L1 blockade. Our labs have been working together on this project in the Ludwig Center for Metastasis Research for most of the past decade. This interdisciplinary endeavor could lead to a transformation in the treatment of mCRC.