Project 1: Siglec15 as a new target for lung cancer immunotherapy

项目1：Siglec15作为肺癌免疫治疗新靶点

• 批准号: 10203854
• 负责人: Lieping Chen
• 金额: $ 36.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-26 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10203854
• 关键词: AXIN1 protein; Ablation; Adverse event; Antibodies; Antibody Therapy; Antigens; Basic Science; Binding; Biological Markers; Biological Response Modifiers; Blocking Antibodies; Cancer Biology; Cancer Patient; Cell Culture System; Cells; Cellular Structures; Chemotherapy and/or radiation; Chemotherapy-Oncologic Procedure; Classification; Clinic; Clinical; Clinical Sciences; Clinical Trials; Cytometry; Data; Dose; Flow Cytometry; Foundations; Future; Hodgkin Disease; Homologous Gene; Hospitals; Human; IgG4; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune system; Immunity; Immunofluorescence Immunologic; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Institution; Interferon Type II; Lead; Lectin; Ligands; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Myeloid Cells; Names; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; PDL1 pathway; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Phase II Clinical Trials; Phenotype; Proteins; Research Personnel; Resistance; Role; Safety; Sialic Acids; Solid Neoplasm; Specimen; T cell regulation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translational Research; Tumor Immunity; Tumor Tissue; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Work; anti-4-1BB; antigen-specific T cells; base; biomarker validation; cancer cell; cancer immunotherapy; cancer therapy; checkpoint therapy; cohort; cytokine; design; effective therapy; effector T cell; genome-wide; immune function; immunomodulatory therapies; improved; in vivo; macrophage; melanoma; mouse model; neoplastic cell; novel strategies; patient derived xenograft model; patient response; personalized medicine; potential biomarker; prevent; programmed cell death ligand 1; programmed cell death protein 1; prospective; receptor; resistance mechanism; response; safety testing; sialic acid binding Ig-like lectin; tool; treatment response; treatment strategy; tumor; tumor immunology; tumor microenvironment; validation studies

PROJECT SUMMARY The inability of tumor infiltrating lymphocytes (TILs) to target and kill tumor cells is a major hurdle in treating many malignancies. New treatment strategies that block immune inhibitory mechanisms, such as antibodies that block the interaction of programmed death-1 (PD-1) with its ligand, B7 homolog 1 (B7-H1, also known as PD-L1), have shown promising efficacy in the clinic. Termed checkpoint inhibitor therapy, these drugs have been approved for many indications, including melanoma, Hodgkin lymphoma and lung cancer, and are increasingly being used in combination or in conjunction with other cancer therapies, such as chemotherapy and radiation. Although checkpoint inhibitor treatments have resulted in durable clinical responses in a large proportion of cases, many patients present with tumor types that do not respond to treatment. For instance, ~26% of NSCLC cases, which are negative for B7-H1/PD-L1 and positive for TILs, have been shown to be resistant to anti-PD-1/B7-H1(PD-L1) (anti-PD) therapy. This type of NSCLC, denoted as Type III, is suspected to harbor a mechanism of immune inhibition distinct from other NSCLC types, which has been found to be driven, at least in part, by sialic acid binding immunoglobulin-like lectin 15 (siglec-15). Siglec-15 expression is mutually exclusive from B7-H1/PD-L1 expression in NSCLC cohorts and has been shown to inhibit T cell proliferation and effector function. Blocking of siglec-15 using anti-siglec-15 (S15) monoclonal antibody (mAb) is therapeutic in mouse models and human cell culture systems and results in amplified T cell responses. Based on these findings, a phase I/II, dose escalation, safety and tolerability clinical trial for S15 mAb treatment in patients with advanced or metastatic solid tumors is on-going. Although preliminary studies have generated promising results with regard to the potential efficacy of S15 mAb in the clinic, the mechanism of S15-mediated immune suppression remains unknown. Furthermore, to enhance and improve treatment response rates, more work must be done to identify pertinent biomarkers for S15 mAb therapy and modes that modulate S15 expression. Finally, developing combination strategies that alter the tumor microenvironment (TME), such that conversion of the tumor Type is achieved, is imperative for successful targeting and killing of tumor by immune cells and in attaining increased patient response rates to available checkpoint inhibitor therapies. A newly generated immune PDX (iPDX) mouse model, which uses patient-derived tumor tissue to recapitulate and manipulate immune cell responses in the TME, will be utilized to investigate these topics specifically in the NSCLC setting. A proposed investigator-initiated phase II clinical trial in patients with S15+ advanced NSCLC who have progressed on PD-1 axis inhibitor therapy will evaluate S15 mAb efficacy and support biomarker validation studies. Strategies to combine S15 mAb with other agents, such as anti-FGL1 and anti-4-1BB/CD137, to improve therapeutic effect will also be explored. Taken together, the studies proposed here will improve our understanding of the NSCLC TME and enhance therapeutic approaches.

项目概要 肿瘤浸润淋巴细胞（TIL）无法靶向并杀死肿瘤细胞是治疗的主要障碍 许多恶性肿瘤。阻断免疫抑制机制（例如抗体）的新治疗策略 阻断程序性死亡 1 (PD-1) 与其配体 B7 同源物 1（B7-H1，也称为 PD-L1），在临床上显示出良好的疗效。这些药物被称为检查点抑制剂疗法 已被批准用于多种适应症，包括黑色素瘤、霍奇金淋巴瘤和肺癌，并且 越来越多地与其他癌症疗法联合使用，例如化疗 和辐射。尽管检查点抑制剂治疗已在大量患者中产生了持久的临床反应 在部分病例中，许多患者的肿瘤类型对治疗没有反应。例如， 约 26% 的 NSCLC 病例（B7-H1/PD-L1 呈阴性且 TIL 呈阳性）已被证明是 对抗 PD-1/B7-H1(PD-L1)（抗 PD）治疗具有耐药性。这种类型的 NSCLC，称为 III 型，被怀疑为 具有不同于其他非小细胞肺癌类型的免疫抑制机制，已被发现 至少部分由唾液酸结合免疫球蛋白样凝集素 15 (siglec-15) 驱动。 Siglec-15 表达式为 与 NSCLC 队列中的 B7-H1/PD-L1 表达相互排斥，并已被证明可以抑制 T 细胞 增殖和效应器功能。使用抗 siglec-15 (S15) 单克隆抗体 (mAb) 封闭 siglec-15 在小鼠模型和人类细胞培养系统中具有治疗作用，并导致 T 细胞反应放大。 基于这些发现，S15 mAb 的 I/II 期、剂量递增、安全性和耐受性临床试验 晚期或转移性实体瘤患者的治疗正在进行中。尽管初步研究已 关于 S15 mAb 在临床中的潜在功效、其机制，产生了有希望的结果 S15 介导的免疫抑制仍然未知。此外，加强和改善治疗 反应率，必须做更多的工作来确定 S15 mAb 治疗的相关生物标志物和模式 调节S15表达。最后，开发改变肿瘤微环境的组合策略 （TME），从而实现肿瘤类型的转化，对于成功靶向和杀死肿瘤细胞至关重要 免疫细胞对抗肿瘤并提高患者对可用检查点抑制剂的反应率 疗法。新生成的免疫 PDX (iPDX) 小鼠模型，使用患者来源的肿瘤组织来 概括和操纵 TME 中的免疫细胞反应，将用于研究这些主题 特别是在 NSCLC 环境中。拟议的研究者发起的针对 S15+ 患者的 II 期临床试验 使用 PD-1 轴抑制剂治疗取得进展的晚期 NSCLC 将评估 S15 mAb 的疗效并 支持生物标志物验证研究。将 S15 mAb 与其他药物（例如抗 FGL1）联合使用的策略 以及抗4-1BB/CD137，以提高治疗效果也将被探索。综合起来，研究 这里提出的建议将提高我们对 NSCLC TME 的理解并增强治疗方法。