Tumor Immune Profiling to Optimize Clinical Trial Readiness in Basal Cell Nevus Syndrome

肿瘤免疫分析可优化基底细胞痣综合征的临床试验准备

基本信息

批准号：
10046642
负责人：
DAVID RINSEY BICKERS
金额：
$ 20.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2020-07-21 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046642
关键词：
Adverse event Affect Alleles Animal Model Antibodies Antitumor Response Area Basal Cell Nevus Syndrome Basal cell carcinoma CD8-Positive T-Lymphocytes CTLA4 gene CXCL10 gene CXCL9 gene CXCR3 gene Cells Clinical Clinical Research Clinical Trials Cytometry Data Dendritic Cells Development Disease Disease remission Double-Blind Method Erinaceidae FOXP3 gene Fatal Outcome Fostering Future Genetic Engineering Germ-Line Mutation Growth Growth and Development function HLA-DR Antigens Hereditary Disease Human Immune Immune checkpoint inhibitor Immune response Immunofluorescence Immunologic Immunologic Monitoring Immunologics Immunotherapeutic agent Individual Infiltration Inflammatory Knowledge Laboratories Lesion MHC Class I Genes Malignant Neoplasms Modeling Morbidity - disease rate Mus Mutation Neoplasm Metastasis Nivolumab Operative Surgical Procedures PTCH gene Pathogenesis Pathologic Patients Pattern Peripheral Phenotype Placebos Population Predisposition Property Randomized Readiness Recurrence Regulatory T-Lymphocyte Reporting Research Resistance Rhabdomyosarcoma Risk Role Skin T-Lymphocyte Testing The Sun Treatment Efficacy Treatment outcome Tumor Burden Tumor-infiltrating immune cells Work anti-PD-L1 therapy arm base bench to bedside chemokine chemokine receptor clinical development cost cytokine early childhood immune checkpoint blockade immunogenic immunoregulation improved inhibitor/antagonist medulloblastoma mouse model neoplastic cell novel novel therapeutics phase II trial preclinical study prevent programmed cell death protein 1 recruit response side effect skin disorder smoothened signaling pathway targeted agent targeted treatment therapy outcome tool treatment strategy tumor tumor initiation tumor microenvironment tumor progression tumor-immune system interactions tumorigenic

项目摘要

SUMMARY Germline mutations in PTCH underlie basal cell nevus syndrome (BCNS), a dominantly inherited disorder also known as Gorlin-Goltz syndrome, in which affected individuals manifest accelerated Hh signaling, leading to inordinate tumor burden that requires multiple, costly and often mutilating surgical procedures. Moreover, BCNS patients develop multiple BCCs in sun-protected areas illustrating their unique tumor susceptibility. Except for tumor-intrinsic Hh signaling, mechanisms underpinning the spontaneous growth and development of BCCs remain unclear. Our group has fostered bench-to-bedside clinical trials with targeted agents in these patients, ultimately leading to FDA approval of the SMO inhibitor (SMOi) vismodegib for treatment of advanced BCCs. Despite substantial anti-tumor efficacy, a major challenge with SMOi has been the emergence of clinical resistance and significant tumor recurrence, as well as intolerable side-effects causing half or more patients to discontinue treatment. Additional preclinical and clinical studies from our group and others clearly indicate that Hh signaling inhibition alone may be necessary but insufficient to permanently eradicate BCCs. This indicates a need to develop novel treatment strategies to ameliorate the limitations of current SMOi’s to improve treatment outcomes. Utilizing our genetically engineered Ptch1+/-/SKH-1 mouse model that faithfully recapitulates the pathogenesis of human BCNS BCCs, we have demonstrated that (i) Hh signaling promotes accumulation of FoxP3+ cells and increases pro-tumorigenic cytokines and chemokines in Ptch1-deficient skin; (ii) SMO inhibition increases CD8+ cells and CXCL10/11, chemokines involved in T cell recruitment; and (iii) treatment of BCC- bearing Ptch1+/-/SKH-1 with anti-PD-1 results in significant tumor regression. These data, together with recent reports showing efficacy of immune checkpoint inhibitors (anti-CTLA4 or anti-PD-1) in human BCCs, strongly support the role of immune mechanisms in BCC growth, and underscore the potential utility of combined SMO and immune checkpoint blockade to reduce tumor burden. To facilitate a future multi-center, single-arm trial of combined therapy of vismodegib and nivolumab (humanized monoclonal anti-PD-1 antibody) in BCNS patients, this application aims to define tumor immune correlates relevant to BCNS microenvironments in Ptch1+/-/SKH-1 mice. In Aim 1, we will characterize immune cell populations and determine the immunologic mechanisms relevant to Hh signaling, and in Aim 2, we will comprehensively define tumor immune profiles and elucidate immunologic correlates predictive of anti-tumor responses to vismodegib and PD-1 blockade.

概括 PTCH 的种系突变是基底细胞痣综合征 (BCNS) 的基础，BCNS 也是一种显性遗传性疾病被称为 Gorlin-Goltz 综合征，受影响的个体表现出加速的 Hh 信号传导，导致过度的肿瘤负担，需要多次、昂贵且常常会造成损伤的外科手术。患者在受阳光保护的区域会出现多个基底细胞癌，这表明他们具有独特的肿瘤易感性。肿瘤固有的 Hh 信号传导、BCC 自发生长和发育的机制目前尚不清楚，我们的团队已经在这些患者中开展了靶向药物的临床试验，最终导致 FDA 批准 SMO 抑制剂 (SMOi) vismodegib 用于治疗晚期 BCC。尽管具有显着的抗肿瘤功效，SMOi 的一个主要挑战是临床应用的出现耐药性和显着的肿瘤复发，以及导致一半或更多患者无法忍受的副作用我们小组和其他人的其他临床前和临床研究明确表明：单独抑制 Hh 信号可能是必要的，但不足以永久消除 BCC。需要开发新的治疗策略来改善当前 SMOi 的局限性，从而改善治疗利用我们的基因工程 Ptch1+/-/SKH-1 小鼠模型忠实地再现了结果。在人类 BCNS BCC 的发病机制中，我们已经证明 (i) Hh 信号传导促进 FoxP3+ 细胞并增加 Ptch1 缺陷皮肤中的促肿瘤细胞因子和趋化因子 (ii) SMO 抑制；增加 CD8+ 细胞和 CXCL10/11（参与 T 细胞募集的趋化因子）；以及 (iii) 治疗 BCC- 携带 Ptch1+/-/SKH-1 和抗 PD-1 会导致肿瘤显着消退。报告显示免疫检查点抑制剂（抗 CTLA4 或抗 PD-1）对人类 BCC 的功效，强烈支持免疫机制在 BCC 生长中的作用，并强调组合 SMO 的潜在效用和免疫检查点阻断以减少肿瘤负荷，以促进未来的多中心、单臂试验。 vismodegib 和 nivolumab（人源化单克隆抗 PD-1 抗体）联合治疗 BCNS 患者，该应用旨在定义与 Ptch1+/-/SKH-1 中 BCNS 微环境相关的肿瘤免疫相关性在目标 1 中，我们将表征免疫细胞群并确定免疫机制。与 Hh 信号传导相关，在目标 2 中，我们将全面定义肿瘤免疫谱并阐明免疫学关联预测 vismodegib 和 PD-1 阻断的抗肿瘤反应。