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

配备 SA-4-1BBL 免疫检查点刺激器的溶瘤腺病毒用于肺癌免疫治疗

• 批准号: 10197415
• 负责人: Jorge G Gomez-Gutierrez
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197415
• 关键词: Adenoviruses; Agonist; Antigen-Presenting Cells; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cancer Patient; Cell Death; Cells; Clinic; Clinical; Clonal Anergy; Consensus; Cytolysis; Data; Development; Differentiation Antigens; Disease; Distant; Evaluation; Face; Failure; Fiber; Foundations; Gene Delivery; Generations; Goals; Human; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Memory; Immunologist; Immunomodulators; Immunoprevention; Immunotherapeutic agent; Immunotherapy; In Vitro; Intranasal Administration; Legal patent; Life; Ligands; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Memory; Methods; Modeling; Mus; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncolytic; Oncolytic Immunotherapy; Oncolytic viruses; Pathway interactions; Patient-Focused Outcomes; Patients; Predictive Factor; Preventive; Property; Protocols documentation; Recombinant Proteins; Recombinants; Recurrence; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resistance; Role; Serotyping; Splenocyte; System; T cell anergy; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Tumor Antigens; Viral; Work; adaptive immune response; adenoviral-mediated; anti-PD-1; anti-cancer; anti-tumor immune response; cancer cell; cancer immunotherapy; cancer type; cost; cytokine; early phase clinical trial; experience; gene therapy; immune checkpoint; immunogenic cell death; immunoregulation; improved; in vivo; innovation; lung cancer cell; neoplastic cell; novel; oncolytic adenovirus; pleiotropism; prevent; programmed cell death ligand 1; prototype; response; side effect; success; targeted treatment; tumor; tumor eradication; tumor immunology; tumor progression; uptake; vector

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.

项目摘要 尽管免疫检查点抑制剂（ICI）在非小细胞肺癌（NSCLC）中取得了临床成功， 许多患者在最初的反应后经历抵抗或面临潜在的危及生命的可能性， 副作用.一部分NSCLC患者可以从免疫刺激分子，如免疫抑制剂， 检查点刺激物，以加强ICI的治疗效果。我们将4-1BB途径作为一种 强大的免疫检查点刺激，这是至关重要的CD 8 + T杀伤细胞反应的产生和长期， 术语免疫记忆鉴于天然配体在可溶形式下缺乏功能，我们产生了一种新的 一种重组寡聚体形式的激动剂SA-4-1BBL，其具有稳健的免疫刺激功能， 在各种肿瘤模型中显示出免疫预防和免疫治疗功效。的目的 一项提议是开发一种新型的NSCLC特异性病毒递送系统，该系统在肿瘤内表达SA-4-1BBL 治疗该提案建立在我们在开发溶瘤腺病毒递送载体和 SA-4-1BBL重组蛋白作为癌症免疫预防的稳健免疫调节剂的开发 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 原型溶瘤病毒系统将SA-4-1BBL（OAdSA-4-1BBL）递送至NSCLC肿瘤。的 初步结果显示OAdSA-4-1BBL在体外有效地刺激脾细胞增殖， 还具有表达SA-4-1BBL并在体内启动肺肿瘤内复制的能力。这本小说 载体在一个单一的试剂中将溶瘤和免疫原性细胞死亡与共刺激分子结合 （溶瘤免疫疗法）。集合的团队包括PI，他是癌症基因治疗专家， 两名癌症免疫学专家获得专利的共刺激分子SA-4-1BBL， 合作研究者/顾问将使用PI的既定载体进行检测。最终的目标是把这个 肿瘤靶向治疗进入早期临床试验，希望预防目前无法治愈的远处转移。 这是一种反复发作的疾病。假设OAdSA-4-1BBL将显著刺激 免疫系统，从而改善抗肿瘤NSCLC反应。我们将使用以下内容来检验假设 目的：1）评价OAdSA-4- 1BBL介导的体外杀伤作用和免疫应答，2）评估OAdSA-4- 1BBL的治疗作用， OAd-SA-4-1BBL作为体内抗肿瘤化合物的功效。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治疗无效的患者受益。 对已建立的免疫检查点抑制剂具有耐药性，并可能对其他癌症类型产生广泛影响。

项目成果

An Oncolytic Adenovirus Encoding SA-4-1BBL Adjuvant Fused to HPV-16 E7 Antigen Produces a Specific Antitumor Effect in a Cancer Mouse Model.

• DOI: 10.3390/vaccines9020149
• 发表时间: 2021-02-12
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Martinez-Perez AG;Perez-Trujillo JJ;Garza-Morales R;Ramirez-Avila NE;Loera-Arias MJ;Gomez-Gutierrez JG;Saucedo-Cardenas O;Garcia-Garcia A;Rodriguez-Rocha H;Montes-de-Oca-Luna R
• 通讯作者: Montes-de-Oca-Luna R