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

翻译一种新的非霍奇金淋巴瘤联合治疗方法。 弥漫性大B细胞淋巴瘤是最常见的非霍奇金淋巴瘤(NHL)，治疗有限 复发或难治(r/r)设置中的选项。在人类和狗身上也是如此。免疫疗法与 检查点抑制剂(CPIs)对霍奇金淋巴瘤显示出持久的疗效，但对 非霍奇金淋巴瘤。临床上对免疫治疗耐药机制的认识和治疗方法的研究尚不成熟。 提高晚期非霍奇金淋巴瘤和其他癌症患者临床疗效的方法。DLBCL输入 伴犬(CDLBCL)采用类似的化疗方案，其预后也同样较差 R/r设置为人类DLBCL。虽然基因组比较显示突变景观的重叠有限 在犬和人的DLBCL中，肿瘤微环境(TME)的初步比较显示 这两个物种之间的基质和免疫隔膜的保护。因此，cDLBLCL提供了 前瞻性研究临床毒性和临床反应机制的机会 真实的背景，概括了人类癌症的病理、异质性和TME。 水疱性口炎病毒(VSV)是一种快速复制、强大的免疫原性溶瘤病毒(OV)平台， 已被设计用于播散性癌症的安全系统治疗。静脉(IV)VSV治疗 临床前在小鼠肿瘤模型中显示能迅速感染、扩散和杀死肿瘤细胞，并诱导强大的 肿瘤内的免疫渗透，使肿瘤对检查点封锁敏感。ONIX(肿瘤免疫加速器) 是一种新型的双靶向CPI，针对肿瘤免疫抑制的先天机制和适应性机制 增强巨噬细胞和T细胞介导的抗肿瘤免疫应答。我们假设 溶瘤VSV和ONIX将有互补的作用机制(MOA)，协同工作以杀死 通过病毒直接裂解和吞噬肿瘤细胞，增加肿瘤相关抗原(TAA)的可用性， 促进抗原提呈，激活抗肿瘤T细胞反应，增强免疫介导的肿瘤 在r/rDLBCL中杀死并改善临床反应。我们的建议融合了 OV开发的领先机构(梅奥诊所)、比较肿瘤学(明尼苏达大学)和 淋巴瘤免疫疗法(Mayo淋巴瘤孢子)进行兽医试验和相关研究 评价这一新的联合治疗方案治疗慢性DLBCL的安全性和初步疗效。建议数 研究将对静脉注射OV如何感染异种DLBCL肿瘤和 搅动TME；如果这种干扰增强了CPIs(以及潜在的其他免疫疗法)的激活能力 免疫介导的肿瘤杀伤；以及肿瘤结构在临床反应和 无响应。自然发生的cDLBCL固有的异质性将告知这一临床应用。 联合治疗，定义MOA，并确定可以在人类DLBCL中临床探索的生物标记物。

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.