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.

摘要