Translation of a novel combination therapy approach for non-Hodgkin lymphoma

非霍奇金淋巴瘤新型联合治疗方法的转化

• 批准号: 10669751
• 负责人: JAIME F. MODIANO
• 金额: $ 62.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669751
• 关键词: Agitation; Antigen Presentation; Architecture; Biological; Canis familiaris; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Research; Combined Modality Therapy; Companions; Correlative Study; Cytolysis; Data; Diagnosis; Dose; Engineering; Gene Expression Profiling; Genomics; Heterogeneity; Hodgkin Disease; Human; Immune; Immune checkpoint inhibitor; Immunooncology; Immunosuppression; Immunotherapy; Individual; Institution; Intravenous; Lymphoma; Macrophage; Malignant Neoplasms; Measures; Mediating; Methods; Minnesota; Modeling; Mus; Mutation; Non-Hodgkin' s Lymphoma; Oncology; Oncolytic viruses; Outcome; Pathology; Patients; Peptides; Phagocytosis; Prognosis; Recurrent disease; Refractory; Refractory Disease; Regimen; Relapse; Resistance; Resources; Safety; Sampling; Specimen; Systemic Therapy; T cell response; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translations; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Universities; Vesicular stomatitis Indiana virus; Viral; anti-tumor immune response; biomarker identification; cancer heterogeneity; clinical development; clinically actionable; cohort; comparative; design; immune checkpoint blockade; immunogenic; immunoregulation; improved; improved outcome; insight; intravenous administration; large cell Diffuse non-Hodgkin' s lymphoma; nano-string; neoplastic cell; novel; oncolytic Vesicular Stomatitis Virus; patient prognosis; patient response; pre-clinical; prospective; refractory cancer; responders and non-responders; response; response biomarker; single cell sequencing; survival outcome; tool; tumor; tumor microenvironment; virus development

Translation of a novel combination therapy approach for non-Hodgkin lymphoma . Diffuse large B-cell lymphoma is the most common type of Non-hodgkin’s lymphoma (NHL) with limited treatment options in the relapsed or refractory (r/r) setting. This is true in humans and dogs. Immunotherapy with checkpoint inhibitors (CPIs) have demonstrated durable efficacy for Hodgkin’s lymphoma, but poor efficacy for NHL. There is an unmet clinical understand mechanisms of immunotherapy resistance and develop therapeutic approaches to improve clinical response for patients with advanced NHL and other cancers. DLBCL in companion dogs (cDLBCL) is treated with similar chemotherapy protocols and has a similarly poor prognosis in the r/r setting as human DLBCL. While genomic comparison shows limited overlap of the mutational landscape in canine and human DLBCLs, preliminary comparison of the tumor microenvironment (TME) shows conservation of stromal and immune compartments between the two species. Thus, cDLBLCL provide opportunities to prospectively investigate clinical toxicities and mechanisms of clinical response in a clinically realistic setting that recapitulates the pathology, heterogeneity, and TME of human cancers. Vesicular stomatitis virus (VSV) is a rapidly replicating, robustly immunogenic oncolytic virus (OV) platform that has been engineered for safe systemic therapy of disseminated cancer. Intravenous (IV) VSV therapy was shown preclinically in murine tumor models to rapidly infect, spread within, and kill tumor cells, and induce robust intratumoral immune infiltration, sensitizing tumors to checkpoint blockade. ONIx (oncoimmunology accelerator) is a novel, dual targeted CPI that targets both innate and adaptive mechanisms of tumor immune suppression to enhance antitumor immune responses mediated by macrophages and T-cells. We hypothesize that oncolytic VSV and ONIx will have complementary mechanisms of action (MOA), working in concert to kill tumor cells by direct viral lysis as well as phagocytosis, increase availability of tumor associated antigens (TAAs), promote antigen presentation and activate anti-tumor T-cell responses, to enhance immune mediated tumor killing and improve clinical responses in r/r DLBCL. Our proposal merges the expertise and resources of leading institutions in OV development (Mayo Clinic), comparative oncology (University of Minnesota), and lymphoma immunotherapy (Mayo Lymphoma SPORE) to perform a veterinary trial and correlative studies to evaluate the safety and preliminary efficacy of this novel combination therapy in r/r cDLBCL. The proposed studies will yield valuable insights into how an IV administered OV can infect heterogeneous DLBCL tumors and agitate the TME; if this disruption enhances the ability of CPIs (and potentially other immunotherapies) to activate immune mediated tumor killing; and how the tumor architecture differs in the context of clinical response versus non-response. The heterogeneity inherent in naturally occurring cDLBCL will inform the clinical utility of this combination therapy, define MOA, and identify biomarkers that can be explored clinically in human DLBCL.

一种新的非霍奇金淋巴瘤联合治疗方法的翻译。 弥漫性大B细胞淋巴瘤是最常见的非霍奇金淋巴瘤（NHL）类型，治疗有限 在复发或难治性（R/R）设置的选项。这在人类和狗身上都是如此。免疫治疗 检查点抑制剂（CPI）已被证明对霍奇金淋巴瘤具有持久的疗效，但对 NHL。目前临床上对免疫治疗耐药机制的了解和治疗方法的开发尚待解决 改善晚期NHL和其他癌症患者临床反应的方法。DLBCL in 伴侣犬（cDLBCL）用类似的化疗方案治疗，并且在治疗中具有类似的不良预后。 r/r设置为人DLBCL。虽然基因组比较显示突变景观的有限重叠 在犬和人DLBCL中，肿瘤微环境（TME）的初步比较显示， 两个物种之间的基质和免疫区室的保护。因此，cDLBLCL提供 在临床试验中前瞻性研究临床毒性和临床应答机制的机会 再现人类癌症的病理学、异质性和TME的现实环境。 水泡性口炎病毒（VSV）是一种快速复制、强免疫原性溶瘤病毒（OV）平台， 已经被设计用于安全的扩散性癌症的系统治疗。静脉（IV）VSV治疗是 临床前在鼠肿瘤模型中显示出快速感染、在肿瘤细胞内扩散和杀死肿瘤细胞，并诱导鲁棒的 肿瘤内免疫浸润，使肿瘤对检查点阻断敏感。ONIx（肿瘤免疫学加速剂） 是一种新型的双重靶向CPI，靶向肿瘤免疫抑制的先天和适应性机制 以增强由巨噬细胞和T细胞介导的抗肿瘤免疫应答。我们假设 溶瘤VSV和ONIx将具有互补的作用机制（MOA），协同工作， 通过直接的病毒裂解以及吞噬作用来抑制肿瘤细胞，增加肿瘤相关抗原（TAA）的可用性， 促进抗原呈递和激活抗肿瘤T细胞应答，以增强免疫介导的肿瘤 杀死并改善r/r DLBCL的临床反应。我们的建议将以下机构的专业知识和资源 OV开发（马约诊所）、比较肿瘤学（明尼苏达大学）和 淋巴瘤免疫疗法（马约淋巴瘤孢子）进行兽医试验和相关研究， 评估这种新型联合治疗在r/r cDLBCL中的安全性和初步疗效。拟议 研究将产生关于IV施用的OV如何感染异质性DLBCL肿瘤的有价值的见解， 抑制TME;如果这种破坏增强了CPI（以及潜在的其他免疫疗法）激活TME的能力， 免疫介导的肿瘤杀伤;以及肿瘤结构在临床反应与 无应答。天然发生的cDLBCL中固有的异质性将告知这种异质性的临床效用。 本发明的目的是提供一种用于联合治疗的方法，定义MOA，并鉴定可以在人DLBCL中临床探索的生物标志物。