Abstract
Improving efficacy of oncolytic virotherapy remains challenging due to difficulty increasing specificity and immune responses against cancer and limited understanding of its population dynamics. Here, we construct programmable and modular synthetic gene circuits to control adenoviral replication and release of immune effectors selectively in hepatocellular carcinoma cells in response to multiple promoter and microRNA inputs. By performing mouse model experiments and computational simulations, we find that replicable adenovirus has a superior tumor-killing efficacy than non-replicable adenovirus. We observe a synergistic effect on promoting local lymphocyte cytotoxicity and systematic vaccination in immunocompetent mouse models by combining tumor lysis and secretion of immunomodulators. Furthermore, our computational simulations show that oncolytic virus which encodes immunomodulators can exert a more robust therapeutic efficacy than combinatorial treatment with oncolytic virus and immune effector. Our results provide an effective strategy to engineer oncolytic adenovirus, which may lead to innovative immunotherapies for a variety of cancers.
Highlights
Improving efficacy of oncolytic virotherapy remains challenging due to difficulty increasing specificity and immune responses against cancer and limited understanding of its population dynamics
We develop a sensory switch circuit which is about 6.5 kb in length and establish a hierarchical assembly method to efficiently load the circuits into adenoviral vector backbone, which can control adenoviral replication and coexpression of immune effectors, such as human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), single-chain variable fragments against either programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1)
We demonstrate the modularity of our circuit design by changing immunomodulatory genes, and confirm the high selectivity of programmed oncolytic virus to kill a variety of hepatocellular carcinoma (HCC) cancer cells in cell cultures and in mouse models
Summary
Improving efficacy of oncolytic virotherapy remains challenging due to difficulty increasing specificity and immune responses against cancer and limited understanding of its population dynamics. Systemic treatment of immunomodulators either alone or in combinations frequently cause severe side effect[4] These studies highlight a continuous advancement and a large unmet demand in cancer immunotherapy to explore efficient approaches to locally modulate immunological state in tumor microenvironment with reduced side effect. Many oncolytic viruses alone only cause weak immune responses, therapeutic efficacy of oncolytic virus against tumors can be greatly enhanced by encoding and locally releasing cytokines and chemokines, which helps overcoming immunosuppression in tumor microenvironment with reduced side effect compared to systematic administration of immunomodulators[6,7,8,9]. The loading capacity of replication-competent adenoviral vector limits accommodation of sophisticated gene circuits and modifying OV is still costly and inefficient by using a ‘trial-and-error’ method, which demands an effective engineering framework to facilitate the development of OV18,19
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