Imaging Acidosis and Immune Therapy in PDAC

PDAC 中的影像学酸中毒和免疫治疗

基本信息

批准号：
10333224
负责人：
Arig A Ibrahim Hashim
金额：
$ 66.98万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
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/10333224
关键词：
Acidity Acidosis Acids Address Affect Bicarbonates Biodistribution Bolus Infusion Buffers Carbon Dioxide Cell Line Cells Chemicals 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

项目摘要

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一种，并且对所有癌症都有抵抗力尽管存在这种阻力，但仍有不少于 12 种开放的临床疗法。研究用检查点封锁 IT 治疗 PDAC 的试验有多种机制可以实现。解释了这种抵抗，包括 PDAC 肿瘤的酸中毒，这是由于糖酵解率高与灌注不良相结合，将活化的 T 细胞置于酸性条件下会严重抑制其活性。我们已经证明口服 NaHCO3 可中和小鼠模型中的肿瘤酸中毒。 PDAC 可以显着改善对检查点封锁的反应，但 I/IIa 期临床。碳酸氢盐的试验未能增加剂量，因此迫切需要开发临床上可行的药物。达到相同结果的替代方案，即中和体内肿瘤酸度以与IT结合。旨在中和肿瘤酸度的疗法直接是经过临床测试的 CEACAM6 靶向脲酶（L- DOS47，Helix Biopharma）将内源性尿素裂解成两个 NH4+ 和一个 CO2，从而碱化局部。 pH 值和该试剂将是我们拟议研究的主要焦点。我们将使用这些方法来检验以下假设：用 L-DOS47 中和肿瘤酸度将与 PDAC 小鼠模型中的检查点封锁相加或协同。支持这些假设，但在开始之前我们需要填补知识空白初步数据显示，L-DOS47 与免疫治疗相结合的临床试验可改善疗效。在 Panc02 肿瘤中联合 L-DOS47 进行检查点阻断；我们计划在当前的工作中将其扩展到更多生物医学相关的模型。 3 个目标：目标 1 将使用分子成像确定这些药物的原位药效学 (PD) 1.1) pH 和 1.2) 酶活性，以优化给药方案以实现酸中和。我们将把这些药物与检查点阻断（抗 PD1 和抗 PD-L1）结合起来，以改善肿瘤控制旨在表达 CEACAM6 的 PDAC 小鼠模型（Panc02、UN-KPC960/961）。其目标是开发可在治疗前预测反应的成像生物标志物，以及在治疗期间监测反应，目标 3 将解决酸性 pH 值的基本问题。初步数据表明 pHe 的酸化会引起微妙但显着的变化。 pHi 下降，这可能是导致随后 T 细胞停滞的原因。 Ca2+ 信号动力学的破坏，导致 NFAT 分布的改变，以及是否存在差异与酸适应或未接触酸的癌细胞和成纤维细胞相比，T 细胞对酸中毒的敏感性。本研究完成后，我们将开发出一种可临床转化的方法来改善 IT 领域 PDAC 以及对酸抑制机制的进一步了解。