Imaging Acidosis and Immune Therapy in PDAC

PDAC 中的影像学酸中毒和免疫治疗

• 批准号: 10088425
• 负责人: Robert J. Gillies
• 金额: $ 68.35万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10088425
• 关键词: Acidity; Acidosis; Acids; Address; Affect; Bicarbonates; Biodistribution; Bolus Infusion; Buffers; Carbon Dioxide; Cell Line; Cells; Chemicals; Cleaved cell; Clinical; Clinical Trials; Clinical Trials Design; Data; Dose; Drops; Drug Kinetics; Engineering; Female; Fibroblasts; Flow Cytometry; Glycolysis; Habitats; Image; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunotherapy; Impairment; Implant; In Situ; Injections; KRASG12D; Knowledge; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolic; Methods; Modeling; Monitor; Mus; Oral; PET/CT scan; Pancreatic Ductal Adenocarcinoma; Perfusion; Pharmacodynamics; Phase; Physiological; Positron-Emission Tomography; Resistance; Respiration; Schedule; Signal Transduction; System; T cell therapy; T-Cell Activation; T-Lymphocyte; Taste Perception; Testing; Therapeutic; Time; Transactivation; Translating; Tumor-Derived; Urea; Urease; Work; alkalinity; anti-CTLA4; anti-PD-1; anti-tumor immune response; cancer cell; clinically translatable; effector T cell; enzyme activity; expectation; extracellular; fluorodeoxyglucose positron emission tomography; imaging biomarker; immune checkpoint blockade; improved; in vivo; magnetic resonance spectroscopic imaging; male; melanoma; molecular imaging; mouse model; neoplastic cell; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; programmed cell death ligand 1; programmed cell death protein 1; radiomics; response; response biomarker; secondary endpoint; therapy design; treatment effect; tumor; tumor growth; tumor-immune system interactions

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the most lethal of all cancers and is largely resistant to all therapies, including immune therapies (IT). Despite this resistance, there are no fewer than 12 open clinical trials investigating treatment of PDAC with checkpoint blockade IT. There are multiple mechanisms that can account for this resistance, including the acidosis of PDAC tumors, which is due to high rates of glycolysis in combination with poor perfusion. Placement of activated T cells in acidic conditions profoundly inhibits their effector functions. We have shown that neutralization of tumor acidosis with oral NaHCO3 in murine models of PDAC can lead to dramatic improvements in response to checkpoint blockade. However, phase I/IIa clinical trials with bicarbonate failed to dose escalate. Thus, there is a compelling need to develop clinically viable alternatives to achieve the same result, viz. neutralization of tumor acidity in vivo in order to combine with IT. A therapy designed to directly neutralize tumor acidity is a clinically-tested CEACAM6-targeted urease (L- DOS47, Helix Biopharma). This cleaves endogenous urea into two NH4+ and one CO2, thus alkalinizing local pH, and this agent will be our primary focus in the proposed studies. We will use these approaches to test the hypothesis that neutralizing tumor acidity with L-DOS47 will be additive or synergistic with checkpoint blockade in mouse models of PDAC. Our preliminary data support these hypotheses, yet there are gaps in our knowledge that need to be filled prior to embarking on clinical trials combining L-DOS47 with immune therapy. Preliminary data have shown improved response to checkpoint blockade in combination with L-DOS47 in Panc02 tumors; an immune competent model of PDAC, and we plan to expand this to more biomedically relevant models in the current work. These will be addressed in 3 Aims: Aim 1 will determine the in situ pharmacodynamics (PD) of these agents using molecular imaging of 1.1) pH and 1.2) enzyme activity in order to optimize dosing schema to achieve acid neutralization. In Aim 2, we will combine these agents with checkpoint blockade (anti-PD1 and anti-PD-L1) to improve tumor control in mouse models of PDAC engineered to express CEACAM6 (Panc02, UN-KPC960/961). A secondary endpoint in this aim will be to develop imaging biomarkers of response that can be used prior to therapy to predict, and during therapy to monitor, response. Aim 3 will address the fundamental question of HOW an acidic pH induces T cell stasis. Preliminary data have shown that acidification of pHe induces a subtle, yet significant, drop in pHi, which may be responsible for subsequent T-cell stasis. We will also investigate whether there is a disruption of Ca2+ signaling dynamics, leading to altered NFAT distribution, and whether there is a differential sensitivity of T-cells to acidosis, compared with acid-adapted or acid-naïve cancer cells and fibroblasts. At the completion of this study, we will have developed a clinically translatable approach to improve IT in PDAC as well as an improved understanding of the mechanism underlying acid inhibition.

抽象的 胰腺导管腺癌（PDAC）是所有癌症中最致命的，在很大程度上对所有癌症具有抗药性 疗法，包括免疫疗法（IT）。尽管这种抵抗力，但不少于12个开放临床 通过检查点封锁IT调查PDAC处理的试验。有多种机制可以 考虑到这种抗性，包括PDAC肿瘤的酸中毒，这是由于高糖酵解速率 结合不良的灌注。活化的T细胞在酸性条件下的放置深刻抑制其 效应器功能。我们已经表明，在鼠模型中，肿瘤酸中毒与口服Nahco3的神经化 PDAC可以响应检查点封锁而导致急剧改进。但是，I/IIA期临床 碳酸氢盐试验未能升级。那是有必要开发临床可行的 取得相同结果的替代方案，即。体内肿瘤酸度的神经化以与之结合。一个 旨在直接中和肿瘤酸度的治疗是一种经过临床测试的CECAM6靶向尿素（L-） DOS47，Helix Biopharma）。这将内源性尿素切割成两个NH4+和一个二氧化碳，从而碱化局部 pH，该药物将是我们在拟议的研究中的主要重点。 我们将使用这些方法来检验以下假设，即用L-DOS47中和肿瘤酸度将 在PDAC的鼠标模型中，与检查点封锁是加性或协同作用。我们的初步数据 支持这些假设，但是我们的知识中有一些差距需要填补 将L-DOS47与免疫治疗相结合的临床试验。初步数据显示了对 检查点封锁与PANC02肿瘤中的L-DOS47结合使用； PDAC的免疫能力模型， 我们计划将其扩展到当前工作中更具生物医学相关的模型。这些将被解决 在3个目标中：AIM 1将使用分子成像来确定这些药物的原位药物脱粒动力学（PD） 1.1）pH和1.2）酶活性，以优化剂量模式以实现酸神经化。在AIM 2中， 我们将将这些试剂与检查点封锁（抗PD1和抗PD-L1）相结合，以改善肿瘤控制 PDAC的鼠标模型设计为表达CEACAM6（PANC02，UN-KPC960/961）。次要端点 在此目标中，将开发成像生物标志物的反应生物标志物，可以在治疗前预测和 在治疗过程中，应答。 AIM 3将解决酸性pH的基本问题 诱导T细胞停滞。初步数据表明，PHE的酸化可引起微妙但又显着的 下降PHI，可能导致随后的T细胞滞留。我们还将调查是否有 CA2+信号传导动力学的破坏，导致NFAT分布发生变化，以及是否存在差异 与适应酸或酸的癌细胞和成纤维细胞相比，T细胞对酸中毒的敏感性。 这项研究完成后，我们将开发一种可翻译的方法来改进它 PDAC以及对抑制酸抑制的机制的理解。