Head & Neck Unit

Location: Royal Marsden

Section: NHS Clinical Research Programme

Head of Unit: Dr C M Nutting MD MRCP FRCR

Highlights

• Completion of in vitro and in vivo laboratory studies that have resulted in patient recruitment into a Phase I trial of human herpes simplex virus expressing GM-CSF plus radical chemo-radiotherapy in patients with stage III and IV head and neck cancer
• Demonstration of the cytotoxic effect of combining oncolytic reovirus with radiation in tumour cell lines in vitro and in vivo and subsequent translation of this work into a Phase I trial in the clinic
• Analysis of the effect of combining genetic radioisotopic therapy with external beam radiotherapy and novel radiosensitising agents

Recent Aims

• Continued patient recruitment into 4 ongoing trials of gene therapy/virotherapy in The Royal Marsden Hospital
• Progress towards opening a Cancer Research UK funded Phase I trial of virally-directed enzyme prodrug therapy using a selectively replication-competent adenovirus

Enhancement of the Radiation Response through Targeted Gene Delivery

Investigators: KJ Harrington, C White, K Twigger, T Menghistu, M Hingorani, L Vidal, V Agrawal

The goal of this team is to combine novel targeted therapy approaches with radiation in the treatment of cancer. In particular, the aim is to develop strategies for the use of vectors for the delivery of genes that will enhance the tumour response to external beam or radioisotopic irradiation. Initial studies have focused on the use of virus-directed enzyme prodrug therapy (VDEPT) using replication-deficient adenoviral vectors containing the E. coli nitroreductase (NTR) gene with the CB1954 prodrug. This approach has been shown to enhance radiation-induced cell death in vitro and in vivo. Direct delivery of radiosensitising and/or immunomodulatory genes in the form of tumour necrosis factor alpha (TNF alpha) and/or GM-CSF by replication-competent herpes simplex virus-1 (HSV-1) vectors has been investigated in vitro and in vivo. These studies have formed the basis of a successful GTAC submission to conduct a Phase I trial of intratumoural herpes simplex virus in combination with chemoradiotherapy in stage III and IV head and neck cancer. Recruitment to this study is ongoing. We have demonstrated that oncolytic Reovirus Type 3 (Dearing) enhances the effect of radiation in vitro and in vivo. A Phase I trial of this agent in combination with short-course palliative radiotherapy is currently underway. Viral vectors expressing the sodium iodide symporter (NIS) gene have been made as a means of exploiting the diagnostic and therapeutic role of radioactive iodine in cancers other than thyroid cancer. Constructs containing different tissue- and tumour-specific promoters have been designed. In vitro analyses have been performed in non-thyroid solid cancer (colorectal, head and neck) models. Combination studies with external beam radiotherapy and novel radiosensitisers are also ongoing. A new project is examining the potential use of free tissue transfer by microsurgical techniques as a means of delivery gene therapy into a post-operative surgical bed.

This programme of preclinical work is being carried out in the context of an active programme of clinical research for patients with head and neck cancer at The Royal Marsden and St George's Hospitals. A Phase I/II study of intratumoural administration of a replication-competent HSV-1 vector that expresses GM-CSF in patients with cutaneous relapse of cancer has been completed. A Phase I trial of systemically administered Reovirus Type 3 (Dearing) is nearing completion and will lead to further trials of intravenous Reovirus plus cytotoxic chemotherapy. All of these studies will be supported by laboratory assays of viral persistence, shedding and tumour colonisation performed in the Targeted Therapy Laboratory. A Cancer Research UK sponsored Phase I trial of a modified vaccinia Ankara virus expressing EBNA1 and LMP2 in patients with EBV-associated malignancies has opened to recruitment.

External Funding: Cancer Research UK