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

基本信息

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
项目类别：
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

项目摘要

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）中取得了成功，但许多患者在初步反应后经历了抵抗，或者面临潜在威胁生命的可能性副作用。 NSCLC患者的一部分可以受益于免疫刺激分子，例如免疫检查点刺激剂，以强调ICIS的治疗作用。我们专注于4-1BB途径强大的免疫检查点刺激对于CD8+ T杀手反应的产生至关重要术语免疫记忆。鉴于天然配体以可溶性形式缺乏功能，我们产生了一种小说激动剂SA-4-1BBL的重组寡聚形式，具有强大的免疫刺激功能在各种肿瘤模型中表现出免疫预防和免疫疗法的功效。这个目的建议是开发一种新型的NSCLC特异性病毒输送系统，该系统在肿瘤内表达SA-4-1BBL 用于治疗。这项建议是基于我们开发溶瘤腺病毒递送工具的专业知识以及开发SA-4-1BBL重组蛋白作为癌症免疫预防的可靠免疫调节剂和治疗。为了通过减少时间和成本进一步提高翻译潜力，我们开发了一种新颖原型癌性病毒系统将SA-4-1BBL（OADSA-4-1BBL）传递到NSCLC肿瘤。这初步结果表明，OADSA-4-1BBL有效地刺激了体外和还具有表达SA-4-1BBL的能力，并在体内肺部肿瘤内复制。这本小说矢量结合了一种单一药物，结合了溶瘤和免疫原性细胞死亡与共刺激分子（溶瘤免疫疗法）。组装团队包括PI，他是一名癌症基因疗法专家与两名癌症免疫学专家。获得专利的共刺激分子SA-4-1BBL 共同评价器/顾问应与PI的既定向量进行测试。最终目标是移动以肿瘤为目标的治疗进行早期临床试验，希望预防目前无法治愈的远处这种顽固疾病的复发。假设是OADSA-4-1BBL将显着刺激免疫系统，从而改善抗肿瘤NSCLC反应。我们将使用以下来检验假设目的：1）评估OADSA-4-1BBL介导的杀伤效果和体外免疫反应和2）评估治疗 OAD-SA-4-1BBL作为体内抗肿瘤化合物的功效。溶瘤免疫疗法的评估（OADSA-4-1BBL）作为新一代的免疫疗法，可以使治疗患者受益对已建立的免疫检查点抑制剂有抵抗力，并且可能对其他癌症类型具有广泛的影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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