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

项目摘要 肿瘤浸润淋巴细胞（TIL）不能靶向和杀死肿瘤细胞是治疗肿瘤的主要障碍。 许多恶性肿瘤。阻断免疫抑制机制的新治疗策略，如抗体 阻断程序性死亡-1（PD-1）与其配体B7同系物1（B7-H1，也称为 PD-L1）在临床上显示出有希望的疗效。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， 越来越多地与其他癌症疗法（如化学疗法）联合或结合使用 和辐射。尽管检查点抑制剂治疗在大部分患者中产生了持久的临床反应， 在大多数病例中，许多患者的肿瘤类型对治疗无反应。比如说， 约26%的B7-H1/PD-L1阴性和TIL阳性的NSCLC病例已被证明是 抗PD-1/B7-H1（PD-L1）（抗PD）治疗耐药。这种类型的NSCLC，称为III型， 具有不同于其他NSCLC类型的免疫抑制机制，已发现 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表达是 与NSCLC队列中的B7-H1/PD-L1表达相互排斥，并已显示可抑制T细胞 增殖和效应子功能。使用抗siglec-15（S15）单克隆抗体（mAb）阻断siglec-15 在小鼠模型和人类细胞培养系统中具有治疗性，并导致T细胞应答增强。 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。尽管初步研究表明， 在S15 mAb在临床中的潜在疗效、 S15介导的免疫抑制仍然未知。此外，为了加强和改善治疗， 为了提高缓解率，必须做更多的工作来确定S15 mAb治疗的相关生物标志物， 调节S15表达。最后，开发改变肿瘤微环境的组合策略， (TME)，使得实现肿瘤类型的转化，对于成功靶向和杀死肿瘤细胞是必要的。 肿瘤的免疫细胞和实现增加患者的反应率可用的检查点抑制剂 治疗一种新产生的免疫PDX（iPDX）小鼠模型，该模型使用患者来源的肿瘤组织， 概括和操纵TME中的免疫细胞反应，将用于研究这些主题 尤其是在NSCLC的情况下。一项在S15+患者中进行的拟定促发剂启动的II期临床试验 PD-1轴抑制剂治疗后进展的晚期NSCLC患者将评估S15 mAb的疗效， 支持生物标志物验证研究。联合收割机S15 mAb与其他药物（如抗FGL 1）联合的策略 抗4-1BB/CD 137抗体，以提高治疗效果。综合来看，这些研究 本文提出的方法将提高我们对NSCLC TME的认识，并增强治疗方法。

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.