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

• 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
• 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

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.

总结 基底细胞痣综合征（BCNS）是一种显性遗传性疾病， 被称为Gorlin-Goltz综合征，其中受影响的个体表现出加速的Hh信号传导，导致 过度的肿瘤负荷需要多次、昂贵且通常是毁损性的外科手术。此外，BCNS 患者在防晒区域发展出多个BCC，说明他们独特的肿瘤易感性。除了 肿瘤内源性Hh信号，支持基底细胞癌自发生长和发育的机制 仍然不清楚。我们的团队已经在这些患者中进行了靶向药物的临床试验， 最终导致FDA批准SMO抑制剂（SMOi）维莫德吉用于治疗晚期BCC。 尽管具有显著的抗肿瘤功效，但SMOi的主要挑战是临床肿瘤的出现。 耐药性和显著的肿瘤复发，以及无法忍受的副作用，导致一半或更多的患者 停止治疗。我们小组和其他人的其他临床前和临床研究清楚地表明， 单独的Hh信号传导抑制可能是必要的，但不足以永久根除BCC。这表明 需要开发新的治疗策略，以改善目前SMOi的局限性，以改善治疗 结果。利用我们的基因工程Ptch 1 +/-/SKH-1小鼠模型，忠实地再现了 在人类BCNS BCC的发病机制中，我们已经证明了（i）Hh信号传导促进 FoxP 3+细胞，并增加Ptch 1缺陷皮肤中的促肿瘤细胞因子和趋化因子;（ii）SMO抑制 增加CD 8+细胞和CXCL 10/11，参与T细胞募集的趋化因子;和（iii）治疗BCC- 携带Ptch 1 +/-/SKH-1和抗PD-1的肿瘤细胞导致显著的肿瘤消退。这些数据，加上最近 报告显示免疫检查点抑制剂（抗CTLA 4或抗PD-1）在人BCC中的疗效， 支持免疫机制在BCC生长中的作用，并强调联合SMO的潜在效用 和免疫检查点阻断以减少肿瘤负荷。为了促进未来的多中心，单组试验， 维莫德吉和纳武单抗（人源化单克隆抗PD-1抗体）在BCNS患者中的联合治疗， 本申请旨在定义与Ptch 1 +/-/SKH-1中的BCNS微环境相关的肿瘤免疫相关物 小鼠在目标1中，我们将描述免疫细胞群并确定免疫机制 在目标2中，我们将全面定义肿瘤免疫特征并阐明 预测对维莫德吉和PD-1阻断的抗肿瘤应答的免疫学相关性。