Rationally Designed Oncolytic Reovirus-Based Immunotherapy for Hepatocellular Carcinoma
Lead Research Organisation:
University of Birmingham
Department Name: Institute of Immunology & Immunotherapy
Abstract
The incidence of hepatocellular carcinoma (HCC) in the UK has increased more than four-fold since 1990, and worldwide HCC is the second biggest cause of cancer-specific mortality. Very few patients achieve long-term survival, due to late diagnosis and a lack of effective therapies. Encouraging results are now emerging using immune checkpoint modulators (ICMs) that amplify T-cell activity. However, efficacy remains low and ICM-induced high-grade hepatotoxicity can be problematic.
Our published and ongoing work indicates that oncolytic reovirus, an immunotherapeutic wild-type virus, sensitises HCC to subsequent immune checkpoint-modulating therapies, through selective replication in tumour and expression of interferons, thereby providing a complementary and potentially safe combination immunotherapy strategy. For patients with abnormal liver reserves, the potential to reverse hepatic immune tolerance, or to increase hepatotoxicity by immune cell-mediated elimination of hepatitis B/C virus (HBV/HCV)-infected non-malignant hepatocytes must be considered. In addition, HBV/HCV infections can suppress interferons thereby reducing OV-mediated immunotherapy.
Objectives
To rationally establish combinations and schedules of reovirus and immune checkpoint modulators for HCC, based on safety and efficacy.
To define the immunological mechanisms of reovirus-ICM therapy.
To assess the effects of HBV/HCV-induced immunosuppression on reovirus-ICM therapy, and whether optimal HBV/HCV inhibition improves safety and efficacy.
The project will include the following experimental themes.
1. Tissue culture of primary HCC and non-malignant liver samples derived from patients undergoing hepatic surgery.
2. Flow cytometry assessment of the temporal expression dynamics of a panel of co-inhibitory and co-stimulatory checkpoint receptors and their ligands on tissue-resident helper/cytotoxic T-cells NK cells, and antigen presenting cells, following pulsed reovirus stimulation. On this basis, checkpoint receptors that are specifically/preferentially upregulated in HCC samples, in comparison to non-malignant liver samples, will be taken forward.
3. Assessment of the mechanisms of reovirus-induced receptor/ligand upregulation.
4. Functional assessment of NK and T-cell mediated killing of HCC cells, alongside safety assessment using non-malignant hepatocytes.
5. Cell line models of infectious and subgenomic HBV/HCV in BSL 2-3 tissue culture facilities, to determine the effects of HBV and HCV on the efficacy and safety of immunotherapy.
6. In vivo experiments using the most promising immunotherapeutic combinations in immunocompetent models of HCC.
This project will establish the next generation of combination immunotherapies for the treatment of HCC. Your work will also indicate the need to include optimal HBV/HCV inhibition, as a generic component of HCC immunotherapy regimens, particularly those with an interferon-based mechanism of action. We anticipate that successful completion of this project will directly inform phase 1 trials, testing a new generation of potentially effective and safe combination immunotherapies for patients with HCC.
Our published and ongoing work indicates that oncolytic reovirus, an immunotherapeutic wild-type virus, sensitises HCC to subsequent immune checkpoint-modulating therapies, through selective replication in tumour and expression of interferons, thereby providing a complementary and potentially safe combination immunotherapy strategy. For patients with abnormal liver reserves, the potential to reverse hepatic immune tolerance, or to increase hepatotoxicity by immune cell-mediated elimination of hepatitis B/C virus (HBV/HCV)-infected non-malignant hepatocytes must be considered. In addition, HBV/HCV infections can suppress interferons thereby reducing OV-mediated immunotherapy.
Objectives
To rationally establish combinations and schedules of reovirus and immune checkpoint modulators for HCC, based on safety and efficacy.
To define the immunological mechanisms of reovirus-ICM therapy.
To assess the effects of HBV/HCV-induced immunosuppression on reovirus-ICM therapy, and whether optimal HBV/HCV inhibition improves safety and efficacy.
The project will include the following experimental themes.
1. Tissue culture of primary HCC and non-malignant liver samples derived from patients undergoing hepatic surgery.
2. Flow cytometry assessment of the temporal expression dynamics of a panel of co-inhibitory and co-stimulatory checkpoint receptors and their ligands on tissue-resident helper/cytotoxic T-cells NK cells, and antigen presenting cells, following pulsed reovirus stimulation. On this basis, checkpoint receptors that are specifically/preferentially upregulated in HCC samples, in comparison to non-malignant liver samples, will be taken forward.
3. Assessment of the mechanisms of reovirus-induced receptor/ligand upregulation.
4. Functional assessment of NK and T-cell mediated killing of HCC cells, alongside safety assessment using non-malignant hepatocytes.
5. Cell line models of infectious and subgenomic HBV/HCV in BSL 2-3 tissue culture facilities, to determine the effects of HBV and HCV on the efficacy and safety of immunotherapy.
6. In vivo experiments using the most promising immunotherapeutic combinations in immunocompetent models of HCC.
This project will establish the next generation of combination immunotherapies for the treatment of HCC. Your work will also indicate the need to include optimal HBV/HCV inhibition, as a generic component of HCC immunotherapy regimens, particularly those with an interferon-based mechanism of action. We anticipate that successful completion of this project will directly inform phase 1 trials, testing a new generation of potentially effective and safe combination immunotherapies for patients with HCC.
