Oncolytic Adenovirus Armed with SA-4-1BBL Immune Checkpoint Stimulator for Lung Cancer Immunotherapy

项目摘要 尽管免疫检查点抑制剂(ICIS)在非小细胞肺癌(NSCLC)的临床上取得了成功， 许多患者在最初的反应后出现抵抗，或面临潜在生命威胁的可能性。 副作用。一部分非小细胞肺癌患者可以从免疫刺激分子中受益，如免疫 检查点刺激器，以强调ICIS的治疗效果。我们把重点放在4-1BB途径上 强大的免疫检查点刺激，对产生CD8+T细胞杀伤反应和长时间 术语免疫记忆。鉴于天然配体缺乏可溶形式的功能，我们产生了一种新的 激动剂SA-4-1BBL的重组寡聚体形式，具有强大的免疫刺激功能 在不同的肿瘤模型中证明了免疫预防和免疫治疗的有效性。这样做的目的是 建议开发一种新的、非小细胞肺癌特异性的病毒递送系统，在肿瘤内表达SA-4-1BBL 接受治疗。这项建议基于我们在开发溶瘤腺病毒载体方面的专业知识和 SA-4-1BBL重组蛋白作为肿瘤免疫预防强效免疫调节剂的研究进展 和心理治疗。为了通过减少时间和成本进一步提高翻译潜力，我们开发了一种新的 携带SA-4-1BBL(OAdSA-4-1BBL)至非小细胞肺癌肿瘤的溶瘤病毒原型系统。这个 初步结果表明，OAdSA-4-1BBL在体外能有效地刺激脾细胞的增殖， 也具有表达SA-4-1BBL+在体内肺癌内启动复制的能力。这部小说 载体在一种单一试剂中将溶瘤和免疫原性细胞死亡与共刺激分子相结合 (溶瘤免疫疗法)。集合的团队包括PI，他是一名癌症基因治疗专家 和两位癌症免疫学专家。专利的共刺激分子SA-4-1BBL 合作调查员/咨询师将用PI的既定向量进行测试。最终的目标是推动这一点 肿瘤靶向治疗进入早期临床试验，希望防止目前无法治愈的遥远 这种顽固性疾病的复发。假设OAdSA-4-1BBL将显著刺激 免疫系统，从而提高抗肿瘤NSCLC反应。我们将使用以下方法来检验该假设 目的：1)体外评价OAdSA-4-1BBL介导的杀伤效应和免疫应答；2)评价治疗效果 OAD-SA-4-1BBL作为体内抗肿瘤化合物的作用溶瘤免疫治疗的评价 (OAdSA-4-1BBL)作为新一代免疫疗法，可以使目前正在接受治疗的患者受益 对已建立的免疫检查点抑制剂具有抵抗力，并可能对其他癌症类型产生广泛影响。

Project Summary Despite the clinical successes of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC), many patients experience resistance after an initial response or face the possibility of potentially life-threatening side effects. A subset of NSCLC patients could benefit from immunostimulatory molecules, such as immune checkpoint stimulators, to accentuate the therapeutic effects of ICIs. We focused on the 4-1BB pathway as a powerful immune checkpoint stimulatory that is critical to the generation of CD8+ T killer responses and long- term immune memory. Given that the natural ligand lacks function in soluble form, we generated a novel recombinant oligomeric form of an agonist, SA-4-1BBL, that has robust immunostimulatory function with demonstrated immunoprevention and immunotherapy efficacy in various tumor models. The objective of this proposal is to develop a novel, NSCLC-specific, viral delivery system that expresses SA-4-1BBL within the tumor for therapy. This proposal builds on our expertise in developing oncolytic adenoviral delivery vehicles and the development of SA-4-1BBL recombinant protein as a robust immunomodulator for cancer immunoprevention and therapy. To further improve the translational potential by reducing time and cost, we developed a novel prototype oncolytic viral system to deliver SA-4-1BBL (OAdSA-4-1BBL) to NSCLC tumors. The preliminary results show that OAdSA-4-1BBL efficiently stimulates splenocyte proliferation in vitro and also has the capability to express SA-4-1BBL plus initiate replication within lung tumor in vivo. This novel vector combines, in one single agent, oncolytic and immunogenic cell death with a costimulatory molecule (oncolytic immunotherapy). The assembled team includes the PI who is a cancer gene therapy expert aligned with two cancer immunology experts. The patented costimulatory molecule SA-4-1BBL of the coinvestigator/consultant is to be tested with the established vector of the PI. The ultimate goal is to move this tumor-targeted treatment into early clinical trials with the hope of preventing currently incurable distant recurrences of this recalcitrant disease. The hypothesis is that OAdSA-4-1BBL will significantly stimulate the immune system, thereby improving antitumor NSCLC response. We will test the hypothesis using the following aims: 1) evaluate OAdSA-4-1BBL-mediated killing effect and immune response in vitro and 2) assess therapeutic efficacy of OAd-SA-4-1BBL as an anti-tumor compound in vivo. The evaluation of oncolytic immunotherapy (OAdSA-4-1BBL) as a novel generation of immunotherapies could benefit patients whose treatment is currently resistant to established immune checkpoint inhibitors and could have broad implications in other cancer types.