Abstract
BackgroundThe oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible.MethodsThis study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment.ResultsAn Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response.ConclusionThis work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.
Highlights
The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is being tested in combination with immune checkpoint blockade
We initially examined the ability of CVA21 to stimulate Cytotoxic T lymphocyte (CTL) priming using CVA21-sensitive cells (U266B Multiple myeloma (MM) cells and Intercellular Adhesion Molecule 1 (ICAM-1)/KG-1 Acute myeloid leukemia (AML) cells) which, following direct oncolysis, should release damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) to activate myeloid-derived dendritic cells (mDC) and facilitate CTL priming
We have previously demonstrated, using an alternative Oncolytic virus (OV), reovirus, that anti-tumour immunity can occur independently of direct oncolysis [44], to determine if CVA21-mediated oncolysis was required for the successful generation of CTLs, priming assays were repeated using parental-KG-1 and THP-1 cells which, by comparison to ICAM-1/KG-1 and U266B cells, were relatively non-permissive to CVA21 infection and oncolysis; for example, no evidence of viral replication or cell death was observed in THP-1 cells, and only low level replication (~ 130 fold increase in titre at 72 h) and cell death (~ 10% increase at 1pfu/cell) was observed in KG-1
Summary
The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is being tested in combination with immune checkpoint blockade. A recent clinical report demonstrating that OVT can improve the efficacy of the anti-PD-1 immune checkpoint antibody, pembrolizumab, increases their potential clinical applicability [2]. Oncolytic viruses (OVs) can utilize two distinct mechanisms to induce their anti-tumor effects, namely: 1) direct cytotoxicity (oncolysis) following replication and lytic killing of tumor cells [3,4,5], and 2) induction of anti-tumor immunity, which can be mediated by innate and adaptive immune mechanisms [6,7,8]. Despite numerous efforts to enhance the direct lytic potential of OVT, including suppression of host immune responses, the induction of anti-tumor immunity has emerged as a pivotal mechanism for long-term clinical efficacy [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
