Alan Melcher research projects
Improving cancer therapy by systemic administration of oncolytic virusesFunding period: 01 September 2011 to 31 August 2016
Funding scheme: Biological Sciences Committee (BSC) Programme Grants
Funding committee: Science Committee
We have shown that oncolytic viruses (OV) such as reovirus exert their anti-tumour effects by activating anti-tumour immunity, as well as by directly killing cancer cells. Reovirus is well advanced in the clinic, and our own laboratory and patient data has shown that cells in the blood can protect reovirus from neutralization following intravenous injection for delivery to tumours.
Moreover, such carrier cells can be activated by reovirus to acquire immune-mediated anti-tumour effector function.
Aims and objectives:
Within three specific aims, we will develop strategies to improve direct cytotoxic and immune-mediated therapy for melanoma and colorectal cancer by OV following systemic administration. The first two aims focus on tumour-targeted delivery of reovirus.
Aim 1 seeks to enhance the protected delivery of reovirus to tumours by boosting the number of potential carrier cells (granulocytes, monocytes, lymphocytes, dendritic cells) in the blood, using 'cell mobilizing drugs' (granulocyte or granulocyte-macrophage colony stimulating factor, interleukin-2 and FMS-like tyrosine kinase 3 ligand).
We will also test for activation of anti-tumour immune effector function in these cells by reovirus carriage, and for analogous activation by reovirus of normal resident liver immune cells which the virus accesses in vivo.
Aim 2 further addresses improvement in immune- and vascular-mediated systemic reovirus therapy via combinations with immunomodulatory histone deacetylase inhibitors or chemotherapy, including in the context of vascular endothelial growth factor-secreting tumours.
In Aim 3, we will test an alternative lymphoid-targeted systemic OV strategy, using 'Viral Expressed Epitope Library' (VEEL) vaccines. Vesicular stomatitis virus (replication competent or single cycle), will be used as a viral platform to express a full cDNA library derived from melanocyte/melanoma, autologous/allogeneic/xenogeneic tissue to treat melanoma.
Here, the OV acts as an adjuvant to stimulate immune priming against multiple, undefined tumour-associated antigens expressed by the VEEL vaccine.
Established murine in vivo and human in vitro preclinical models of therapy and anti-tumour immune priming will be used. These include readouts of purging of metastatic lymphoid metastases in mice, and experiments using tissue and blood from patients undergoing cancer surgery.
This breadth of analysis is critical for testing whether common principles apply across different model systems, and underpins informed clinical translation.
How the results will be used:
The results of this work will be used to further optimize the use of systemic OV agents and inform the next generation of biological endpoint and therapeutic trials to build on our established clinical platform.