Reprogramming PDAC tumor microenvironment to improve immunotherapy

重编程 PDAC 肿瘤微环境以改善免疫治疗

• 批准号: 10251378
• 负责人: YVES BOUCHER
• 金额: $ 57.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251378
• 关键词: Address; Affect; Angiotensin II; Angiotensin Receptor; Angiotensins; Animal Model; Antitumor Response; Back; Biopsy; Blood Vessels; CD8-Positive T-Lymphocytes; Cancer Center; Cells; Characteristics; Clinical; Clinical Data; Clinical Trials; Collaborations; Combined Modality Therapy; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Dendritic Cells; Desmoplastic; Development; Disease; Extracellular Matrix; Fibroblasts; Fostering; Frequencies; Future; General Hospitals; Genetic Engineering; Goals; Human; Hypoxia; Immune; Immunity; Immunosuppression; Immunotherapy; Implant; Infiltration; Innate Immune Response; Knowledge; Losartan; Malignant Neoplasms; Massachusetts; Mediating; Minority; Mus; Natural Immunity; Neoadjuvant Therapy; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Population; Pre-Clinical Model; Process; Research; Research Personnel; Resectable; Resected; Resistance; Role; Sampling; Signal Transduction; Survival Rate; System; Systemic Therapy; T cell response; T-Lymphocyte; Testing; Therapeutic; Treatment Efficacy; Tumor Immunity; Tumor-infiltrating immune cells; Unresectable; Work; adaptive immunity; base; bench to bedside; cell type; chemoradiation; clinically relevant; cytotoxic; design; efficacy testing; immune checkpoint blockers; improved; inhibitor/antagonist; innovation; insight; macrophage; multidisciplinary; novel; pancreatic ductal adenocarcinoma model; pre-clinical; preclinical study; recruit; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

We have recently shown in preclinical studies using clinically relevant pancreatic ductal adenocarcinoma (PDAC) models that angiotensin system inhibitors (ASIs), including the angiotensin receptor blocker losartan, can enhance the delivery and efficacy of cytotoxic agents by affecting the tumor microenvironment (PNAS 2011, Nat Commun 2013). The mechanisms underlying this benefit include “normalization” of cancer-associated fibroblasts and extracellular matrix (ECM), resulting in blood vessel decompression, improved perfusion, and decreased hypoxia. These exciting preclinical findings formed the basis of an ongoing Phase II clinical trial at Massachusetts General Hospital (MGH), which combines losartan with cytotoxic therapy – FOLFIRINOX and then chemoradiotherapy in unresectable locally advanced PDAC (NCT01821729). An interim analysis of this trial indicates that adding losartan to neoadjuvant cytotoxic therapy doubles the frequency of conversion to resectable tumors (52%) and strikingly improves overall survival (OS) in these PDAC patients. Remarkably, transcriptomic analysis of tumor biopsies from PDAC patients further indicates that ASI treatment not only normalizes ECM-related phenotypes but also upregulates key pathways associated with anti-tumor immunity involving both adaptive (e.g., CD8+ T cells) and innate (e.g., dendritic cells (DCs)) immune components of the PDAC tumor microenvironment. Based on these preclinical and clinical findings, we hypothesize that ASIs in combination with cytotoxic agents will reprogram the heterogeneous, pro-fibrotic, and immunosuppressive PDAC tumor microenvironment to one that is immunostimulatory. We further propose that combining ASIs and cytotoxic agents will enhance the delivery and efficacy of immunotherapies, which until now have had limited or no benefit in PDAC patients. To test these hypotheses, we designed three Specific Aims: 1) Uncover how losartan combined with cytotoxic agents alters tumor microenvironmental components (ECM, blood vessels, hypoxia) and immune cells, in locally advanced PDAC patients; 2) Dissect the causal role of drug- induced adaptive and innate immune cells in the anti-tumor response in orthotopic (implanted and genetically engineered) PDAC models in mice; and 3) Evaluate whether combining ASI-induced tumor microenvironment reprogramming along with cytotoxic therapies enhances the efficacy of immune checkpoint blockers. Based on our preclinical and clinical data, our tightly integrated and multidisciplinary team of investigators, and our bench-to-bedside-and-back research approach, we anticipate that successful completion of these studies will positively impact the development of new treatments for locally advanced PDAC patients who currently have a 5-year survival rate of ~11%. Moreover, because we will actively participate in the PDAC Consortium, the knowledge gained in these studies will be available for other studies of the immune tumor microenvironment in PDAC that are undertaken within the Consortium. Through this work, we will develop innovative approaches to enhance anti-tumor immunity in this intractable disease.

我们最近在使用临床相关的胰腺导管腺癌的临床前研究中表明 （PDAC）模型血管紧张素系统抑制剂（ASI），包括血管紧张素受体阻滞剂氯沙坦， 可以通过影响肿瘤微环境来增强细胞毒药物的递送和功效（PNAS 2011，Nat Commun 2013）。这种益处背后的机制包括癌症相关的“正常化” 成纤维细胞和细胞外基质（ECM），导致血管减压，改善灌注， 缺氧减少。这些令人兴奋的临床前发现构成了正在进行的 II 期临床试验的基础 马萨诸塞州总医院 (MGH)，将氯沙坦与细胞毒疗法 FOLFIRINOX 和 然后对不可切除的局部晚期 PDAC 进行放化疗 (NCT01821729)。对此进行中期分析 试验表明，在新辅助细胞毒治疗中添加氯沙坦可使转化为细胞毒的频率加倍 可切除的肿瘤（52%）并显着提高了这些 PDAC 患者的总生存期 (OS)。值得注意的是， 对 PDAC 患者肿瘤活检的转录组分析进一步表明，ASI 治疗不仅 使 ECM 相关表型正常化，同时上调与抗肿瘤免疫相关的关键途径 涉及适应性（例如 CD8+ T 细胞）和先天性（例如树突状细胞 (DC)）免疫成分 PDAC肿瘤微环境。根据这些临床前和临床发现，我们假设 ASI 与细胞毒性药物组合将重新编程异质性、促纤维化和免疫抑制性 PDAC肿瘤微环境是一种具有免疫刺激性的环境。我们进一步建议将 ASI 结合起来 和细胞毒性药物将增强免疫疗法的传递和功效，迄今为止，免疫疗法已经 对 PDAC 患者的益处有限或没有益处。为了检验这些假设，我们设计了三个具体目标：1）揭示 氯沙坦与细胞毒药物联合使用如何改变肿瘤微环境成分（ECM、血液 局部晚期 PDAC 患者中的血管、缺氧）和免疫细胞； 2）剖析药物的因果作用- 在原位（植入的和遗传的）抗肿瘤反应中诱导适应性和先天免疫细胞 工程）小鼠 PDAC 模型； 3）评估是否结合ASI诱导的肿瘤微环境 重编程与细胞毒性疗法一起增强了免疫检查点阻断剂的功效。基于 我们的临床前和临床数据，我们紧密整合的多学科研究团队，以及我们的 通过从实验室到临床的研究方法，我们预计这些研究的成功完成将 对目前患有局部晚期 PDAC 患者新疗法的开发产生积极影响 5 年生存率约为 11%。而且，由于我们将积极参与PDAC联盟， 这些研究中获得的知识将可用于免疫肿瘤微环境的其他研究 在联盟内进行的 PDAC 中。通过这项工作，我们将开发创新 在这种顽固性疾病中增强抗肿瘤免疫力的方法。

项目成果

Comparing machine learning algorithms for predicting ICU admission and mortality in COVID-19.

• DOI: 10.1038/s41746-021-00456-x
• 发表时间: 2021-05-21
• 期刊: NPJ digital medicine
• 影响因子: 15.2
• 作者: Subudhi S;Verma A;Patel AB;Hardin CC;Khandekar MJ;Lee H;McEvoy D;Stylianopoulos T;Munn LL;Dutta S;Jain RK
• 通讯作者: Jain RK

Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy.

• DOI: 10.1126/scitranslmed.aan5616
• 发表时间: 2017-10-04
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Pinter M;Jain RK
• 通讯作者: Jain RK

Angiotensin Blockade Modulates the Activity of PD1/L1 Inhibitors in Metastatic Urothelial Carcinoma.

• DOI: 10.1016/j.clgc.2021.04.002
• 发表时间: 2021-12
• 期刊: Clinical genitourinary cancer
• 影响因子: 3.2
• 作者: Jain RK;Skelton Iv WP;Pond GR;Naqvi M;Kim Y;Curran C;Freeman D;Nuzzo PV;Alaiwi SA;Nassar AH;Jain RK;Sonpavde G
• 通讯作者: Sonpavde G

Reengineering the Tumor Vasculature: Improving Drug Delivery and Efficacy.

• DOI: 10.1016/j.trecan.2018.02.010
• 发表时间: 2018-04
• 期刊: Trends in cancer
• 影响因子: 18.4
• 作者: Stylianopoulos T;Munn LL;Jain RK
• 通讯作者: Jain RK

Renin-Angiotensin System Inhibitors to Mitigate Cancer Treatment-Related Adverse Events.

• DOI: 10.1158/1078-0432.ccr-18-0236
• 发表时间: 2018-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Pinter M;Kwanten WJ;Jain RK
• 通讯作者: Jain RK