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

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.