A study of Ad-NTR-GMCSF, given via brachytherapy, followed by CB1954 in patients with locally relapsed prostate cancer

Cancer of the prostate is the most common male tumour and approximately 10,000 men die of this disease every year in the UK. In most patients with tumours confined to the prostate, the cancer can be successfully eradicated using surgery or radiotherapy, nevertheless in about 20% of these patients the tumour relapses, initially within the prostate area but then spreads to other organs such as bone, liver, and lymph nodes. There is no effective treatment for relapsed prostate cancer, drugs that induce a decrease of male hormones can provide a temporary benefit but after one or two years of treatment the cancer becomes insensitive to these drugs. We are developing novel gene therapy treatments for prostate tumours which have relapsed within the prostate. In our current clinical trial we use a genetically modified virus to introduce in the cancer cells a ?suicide? gene which is able to convert an inactive compound (?prodrug?) in a powerful anti cancer drug. The modified virus is injected directly in the relapsed prostate tumour then the ?prodrug? is administered intravenously to the patient. When the ?prodrug? reaches the prostate it is rapidly converted by the suicide gene in an anticancer drug and kills the cancer cells which have been infected with the modified virus. This treatment strategy was safe and showed anti tumour efficacy. Building on these observations we are now planning a new clinical trial using an improved virus which will carry the same suicide gene in combination with a gene able to induce a strong immune response against the cancer cells. In addition, we will use a modified virus injection protocol in order to achieve a uniform distribution of the virus within the whole prostate and to improve the anti-tumour efficacy of our system.

We are developing Virus Directed Enzyme Prodrug Therapy (VDEPT) for the treatment of locally relapsed prostate cancer. Our current clinical trial has shown that the delivery of the Nitroreductase (NTR) gene to the cancer tissue using a replication defective adenovirus (CTL102), followed by the prodrug CB1954 is able to induce NTR expression and PSA responses as well as PSA stabilisations. Although the tolerability and the safety profile of CTL102/CB1954 was good, the tumour responses were short lived and viable cancer cells were found in all post treatment biopsies. It is likely that an insufficient distribution of CTL102 within the prostate and the suboptimal activity of CTL102/CB1954 were responsible for the low efficacy of our system. We are now proposing a new Phase I/II clinical trial incorporating two significant improvements relative to the current study.
(1) We plan to increase the activity of the CTL102/CB1954 system using an improved version of CTL102 expressing the gene for the GM-CSF as well as NTR (Ad-NTR-GMCSF). GM-CSF is a key regulator of the immune system which is thought to augment the antitumour response of the host by stimulating the recruitment and activity of dendritic cells. Preclinical observations have shown that GM-CSF is able to enhance the VDEPT induced immune bystander effect. Consistent with these data we have demonstrated that in mouse models the efficacy of NTR/CB1954 was greatly increased when using a vector co-expressing mGM-CSF and NTR compared to either modality used alone.
(2) In our current trial CTL102 is given via ultrasound-guided trans-rectal injection. Although vector delivery via trans-rectal injection is safe and widely used in prostate cancer gene therapy, it is unlikely that this route of administration is able to cover the entire prostate tissue. We plan to improve the distribution of the virus within the prostate using a brachytherapy-type delivery of the viral vector. This type of administration ensures a more homogenous distribution of the virus within the whole prostate and is expected to result in a higher anti-tumour efficacy.
Five groups of 3 patients each will be treated with increasing doses of Ad-NTR-GMCSF followed 48 h later by intravenous CB1954. Safety and feasibility as well as virus pharmacokinetic constitute the primary objectives of the study. Secondary objectives include the assessment of tumour responses, the study of histology in post treatment biopsies and the study of tumour-specific immune responses stimulated by the gene therapy.