Oncolytic Adenoviruses for Glioma Therapy

用于神经胶质瘤治疗的溶瘤腺病毒

• 批准号: 10476408
• 负责人: FREDERICK F LANG
• 金额: $ 31.53万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476408
• 关键词: Adenovirus Infections; Adenoviruses; Aftercare; Age; Animal Model; Antibodies; Attenuated; Biological; Biopsy; Biopsy Specimen; Brain Neoplasms; CD8B1 gene; Canada; Cell surface; Cells; Characteristics; Clinical; Clinical Data; Clinical Trials; Complementary DNA; Cytotoxic T-Lymphocytes; Data; Development; Dose; Ectopic Expression; FDA approved; Foundations; Genes; Glioma; Goals; Hamsters; Hepatitis Delta Virus; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunosuppression; Immunotherapy; In complete remission; Infection; Infiltration; Inflammation; Injections; Interleukin-2; Ligands; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Mus; OX40; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Organ; PD-1 blockade; PD-1 inhibitors; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Proteins; Publishing; Recurrence; Rest; Safety; Specimen; T-Lymphocyte; Testing; Toxic effect; Translations; Tumor Immunity; Tumor Markers; Tumor Virus Infections; Tumor-Infiltrating Lymphocytes; Vertebral column; Viral; Virus; Virus Diseases; Virus Replication; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; antitumor effect; arm; base; checkpoint receptors; clinical application; combinatorial; effective therapy; first-in-human; immune checkpoint; immunotherapeutic virotherapy; improved; inhibitor; next generation; novel; oncolytic adenovirus; oncolytic virotherapy; pembrolizumab; pre-clinical; preclinical study; prognosis biomarker; prognostic value; programmed cell death protein 1; radiological imaging; receptor; response; response biomarker; synergism; tumor; tumor microenvironment; tumor necrosis factor ligand superfamily member 4

SUMMARY: PROJECT 1 To improve the notoriously poor outcome of patients with malignant gliomas, we developed a novel oncolytic adenovirus, Delta-24-RGD, that selectively replicates in and destroys glioma cells. This virus was tested in a first-in-human Phase I clinical trial in patients with recurrent malignant gliomas (NCT00805376), in which dramatic complete (>95% tumor reduction) and durable (>3 years) responses were observed in 12% of patients. Data from this trial contributed to the groundbreaking paradigm shift demonstrating that the Delta-24-RGD oncolytic virus is a form of immunotherapy. Specifically, analyses of clinical responses and post treatment surgical specimens demonstrated that the oncolytic effect of Delta-24-RGD is followed by an anti-tumor cytotoxic T cell immune response that is capable of resulting in complete tumor regression in a small but significant percentage of patients. These clinical data emphasize the urgent need to amplify the anti-tumor immune response as a means of enhancing the efficacy of Delta-24-RGD. To this end, in this proposal we pursue two convergent approaches whose foundations rest on the concept that immune responses to tumors are mediated by 1) immune checkpoints molecules that attenuate immune responses and against which FDA-approved inhibitors are available, and 2) immune costimulatory molecules which activate immune responses and are ideal to “arm” Delta-24-RGD. In our first approach, we combine Delta-24-RGD with the immune checkpoint inhibitor Pembrolizumab (MERCK), that is directed against the cell surface checkpoint receptor PD-1. We take advantage of the pretreatment biopsy specimens obtained from an ongoing Phase I/II clinical trial of this combination in patients with recurrent gliomas (the CAPTIVE trial, NCT02798406), to not only assess the safety and efficacy of this combination, but also to assess biomarkers for response (Aim 1). In our second approach, we develop and test next-generation Delta-24-RGD viruses that are armed with the cDNA of the ligands of immune co-stimulatory receptors (OX40L, GITRL, 4-1BB). We have already constructed and fully characterized the anti-glioma effects of Delta-24-RGDOX, which carries OX40L, and our data show that Delta-24-RGDOX more efficiently eradicates gliomas compared with Delta-24-RGD in immunocompetent animal models. Therefore, in Aim 2 of this proposal we assess the safety and biological effects of Delta-24-RGDOX on patient tumors in a unique treat-resect-treat clinical trial. Lastly, in Aim 3 we characterize the anti-glioma effects of additional next generation viruses Delta- 24-GREAT (which contains GITRL) and Delta-24-ACT (which contains 4-1BBL) alone and in combination with Delta-24-RGD, to define potential synergy of these viruses. If successful, Project 1 will usher in a new age of oncolytic viral therapies for the treatment of malignant gliomas, for which there is currently no effective treatment.

摘要：项目1 为了改善恶性神经胶质瘤患者的臭名昭著的结果，我们开发了一种新型的溶瘤性 腺病毒，Delta-24-RGD，有选择地复制并破坏神经胶质瘤细胞。该病毒在 对复发性恶性神经胶质瘤患者（NCT00805376）患者的第一期I期临床试验，其中 在12％的患者中，观察到急剧完成（> 95％的肿瘤减少）和耐用（> 3年）。 该试验的数据促成了开创性的范式转移，表明Delta-24-RGD 溶瘤病毒是免疫疗法的一种形式。具体而言，分析临床反应和治疗后 手术标本表明，Delta-24-RGD的溶瘤作用之后是抗肿瘤的细胞毒性 T细胞免疫响应能够导致小但显着的肿瘤消退 患者百分比。这些临床数据强调迫切需要扩增抗肿瘤免疫 响应是提高Delta-24-RGD效率的一种手段。为此，在此提案中，我们追求两个 融合方法的基础取决于介导的免疫反应是介导的概念 by 1）衰减免疫调查的分子免疫切解点，并批准了FDA批准 可以使用抑制剂，2）可激活免疫反应并理想的免疫共刺激分子 要“ ARM” DELTA-24-RGD。在我们的第一种方法中，我们将Delta-24-RGD与免疫检查点抑制剂相结合 Pembrolizumab（默克），针对细胞表面检查点受体PD-1。我们利用 从该组合中正在进行的I/II期临床试验中获得的预处理活检标本 复发性神经胶质瘤的患者（圈养试验，NCT02798406），不仅评估 这种组合，也可以评估生物标志物的反应（AIM 1）。在我们的第二种方法中，我们发展并 测试由免疫共刺激性配体的cDNA武装的下一代Delta-24-RGD病毒 接收器（OX40L，GITRL，4-1BB）。我们已经构建并充分表征了抗神经瘤作用 载有OX40L的Delta-24-RGDOX的数据，我们的数据表明，delta-24-rgdox更有效地是放射线 与免疫能力动物模型中的Delta-24-RGD相比，胶质瘤与Delta-24-RGD相比。因此，在本提案的目标2中 我们评估Delta-24-rgdox对独特治疗治疗中患者肿瘤的安全性和生物学作用 临床试验。最后，在AIM 3中，我们表征了其他下一代病毒delta-delta-的抗神经瘤作用 单独使用24级（包含gitrl）和delta-24-act（包含4-1bbl），并与 Delta-24-RGD，以定义这些病毒的潜在协同作用。如果成功，项目1将迎来一个新时代 溶瘤病毒疗法用于治疗恶性神经胶质瘤，目前尚无有效治疗。