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Targeting immunosuppressive adenosine in patients with metastatic non-small cell lung cancer

靶向免疫抑制腺苷治疗转移性非小细胞肺癌患者

基本信息

批准号：
10593117
负责人：
DAVID P. CARBONE
金额：
$ 38.05万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593117
关键词：
Ablation Adenosine Adenosine A2B Receptor Adverse effects Affect Affinity Animal Model Animals Applications Grants Biology Biopsy Cancer Model Cancer Patient Catabolism Cell Differentiation process Cell Fraction Cells Clinical Research Clinical Trials Collaborations Combination immunotherapy Combined Modality Therapy Data Dendritic Cells Disease Dose Effectiveness Enzymes Evaluation Generations Genetic Growth Immune Immune checkpoint inhibitor Immunity Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Impairment Institution Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Maximum Tolerated Dose Mediating Metabolic Metabolic stress Methods Modeling Molecular Myelogenous Myeloid-derived suppressor cells Natural Killer Cells Nivolumab Non-Small-Cell Lung Carcinoma Outcome PD-1 inhibitors Pathologic Patients Peripheral Blood Mononuclear Cell Phase Phase Ib Clinical Trial Phase Ib Trial Phenotype Preclinical Drug Evaluation Probability Productivity Proteins Purinergic P1 Receptors Receptor Inhibition Receptor Signaling Recommendation Regulation Regulatory T-Lymphocyte Resistance Role Safety Sampling Shapes Signal Transduction Spain T cell response T-Lymphocyte Testing Tissues Tumor Immunity antagonist anti-PD-1 anti-PD1 antibodies anti-tumor immune response blood treatment checkpoint inhibition chemotherapy clinical application cohort design ecto-nucleotidase efficacy evaluation extracellular imaging approach imaging modality immunoregulation improved novel novel strategies novel therapeutic intervention pharmacologic phenotypic biomarker pre-clinical preclinical study programmed cell death protein 1 receptor response safety assessment stress reduction therapeutic target tumor tumor growth tumor microenvironment

项目摘要

SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) have transformed the management of patients with metastatic non-small cell lung cancer (NSCLC). Unfortunately, over 50% of patients do not respond to these therapies. Combination strategies with chemotherapy-ICIs show progress, but long-term responses remain rare, pointing to the role for other tumor-associated mechanisms affecting functionality of immune cells. Adenosinergic signaling has recently emerged as a powerful immuno-metabolic regulator within the tumor microenvironment (TME) exploited by tumors to promote their growth and suppress immunity. Preclinical studies on interference with adenosine generation or signaling through A2A and A2B adenosine receptors (A2BAR) have demonstrated efficacy in relieving this immunosuppression by reducing stress in the TME and decreasing expression of key adenosine-generating enzymes, thereby enhancing efficacy of immune checkpoint inhibition. A2BAR blockade in particular enhanced anti-tumor immunity through both a reduction in myeloid-derived suppressor cell differentiation and an enhancement of the capacity of dendritic cells to evoke anti-tumor T cell responses. These findings provide strong rationale for clinical applications of A2BAR antagonists in combination with current ICIs. To determine whether disruption of A2BAR signaling has the potential to improve upon single agent PD-1 immunotherapy, we propose a phase Ib clinical trial testing the A2BAR antagonist PBF-1129 in combination with nivolumab in patients with metastatic NSCLC. The primary objective of the clinical study is to evaluate the safety and tolerability of combination PBF-1129 with nivolumab; preliminary evidence of efficacy will be evaluated in an expansion cohort. Analysis of pre- and on- treatment blood and tumor samples will be conducted to evaluate the correlation between and immunological parameters and adenosine generation and signaling, and to evaluate the efficacy of PBF-1129 in targeting adenosine-mediated immunosuppression. Finally, we intend to further elucidate mechanisms of metabolic TME and immune regulation by adenosine in pre-clinical cancer models and test the combined PBF-1129/anti-PD-1 approach to ameliorate metabolic TME using a novel imaging modality. Together, we expect that A2BAR antagonist treatment combined with nivolumab will be a safe, effective approach targeting different mechanisms of immunosuppression and tumor growth in metastatic NSCLC patients, that we will uncover immunological profiles reflective of adenosinergic signaling disruption in these patients, and that we will demonstrate the utility of a novel combined imaging approach for evaluation of adenosine targeting in the TME.

摘要/文摘