Information for Doctors

Crusade Laboratories is involved in a variety of pre-clinical research programmes, and in several clinical trials. At the centre of our research is the selectively replication competent HSV mutant that fails to express the virulence factor ICP34.5, known as HSV1716.

Frequently asked questions

Please select a question below to be taken straight to the answer:

• What is the basis of using a HSV mutant?
• What pre-clinical research is Crusade engaged in?
• What is Crusade’s Clinical trial Portfolio?
• Are there any relevant references for previous trials?
• Are there any ongoing clinical trials or trials to start in the near future?
• I have a patient who might be suitable for an ongoing trial. Which sites take part in the trial? Whom do I contact for more information?

1. What is the basis of using a HSV mutant?
HSV is one of the best-characterised human viruses. The entire genome of the HSV-1 strain 17 (the parent strain from which HSV1716 was derived) has been sequenced, and the pathogenesis of HSV has been extensively studied. There is much clinical experience dealing with HSV infections, and safe and clinically proven anti-viral therapy exists for HSV infections.

The terminal 1kb of the long repeat region (RL) of the genome of HSV-1 contains the RL1 gene whose product ICP34.5 confers virulence. Deletion or mutation of the RL1 gene results in HSV which is incapable of replicating in the central nervous system and does not cause encephalitis. The most promising selectively replication competent HSV mutants are those that fail to express the virulence factor ICP34.5. Of these, HSV1716 is the least neurovirulent selectively replication competent HSV-1 mutant characterised to date and thus is a leading candidate for use as a tumour therapy agent. The phenotype of HSV1716 has been extensively characterised in vitro and in vivo.

2.What pre-clinical research is Crusade engaged in?

PRE-CLINICAL PROGRAMMES
Crusade's pre-clinical activities are divided into two main areas:

• development of its enhanced oncolytics portfolio: HSV1716 is readily modified to include additional gene inserts. Modified HSV1716 retains is selectively replication-competent nature, and thus the safety and tolerability of the original virus. The inserted genes are expressed as proteins in infected cells to cause targeted synergistic cell kill within tumours through a range of possible mechanisms.
• development of HSV1716 variants as gene delivery agents: Herpes simplex viruses can also be manipulated to cause prolonged foreign gene expression by further attenuating the viruses and by altering the virus-specific promoters under which the chosen genes are inserted. In this way, it is envisaged that HSV1716 can be used as a powerful gene delivery tool. Research into methods to selectively target specific tissues is advanced and ongoing.

3. What is Crusade’s Clinical trial Portfolio?

CLINICAL TRIALS PORTFOLIO

The following studies are planned or have been completed.

4. Are there any relevant references for previous trials?

Rampling R, Cruickshank G, Papanastassiou V, et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther 2000;7(10):859-66.

MacKie RM, Stewart B, Brown SM. Intralesional injection of herpes simplex virus 1716 in metastatic melanoma. Lancet 2001;357(9255):525-6.

Papanastassiou V, Rampling R, Fraser M, et al. The potential for efficacy of the modified (ICP 34.5(-)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther 2002;9(6):398-406.

Harrow, S., Papanastassiou, V., Harland, J., Mabbs, R., Petty, R., Fraser, M., Hadley, D., Patterson, J., Brown, S. M., Rampling, R. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Ther 2004;11(22):1648-58

5. Are there any ongoing clinical trials or trials to start in the near future?

1716-06 - glioblastoma multiforme

This is Crusade's most advanced study. Regulatory approvals have been obtained and investigational centres recruited. Initiation of the first investigational site is imminent.

The primary objective of this study is to determine whether HSV1716 given by intratumoural administration (either by multipoint microinjection or convection enhanced delivery) is more effective in the treatment of recurrent glioblastoma than a current conventional chemotherapy treatment regime, as measured by overall survival.
Secondary objectives are to compare the quality of life and median progression-free survival of glioblastoma patients undergoing treatment with HSV1716 with the quality of life and median progression-free survival of a similar group of glioblastoma patients undergoing a currently conventional treatment regime.

This multi-centre, multi-dose, comparator-controlled, randomised open-label efficacy study will recruit approximately 380 patients in total. The patient population includes those with proven glioblastoma multiforme who, after surgery and radical radiotherapy, show recurrent tumour as detected by imaging. Patients are allowed to have received concomitant and adjuvant temozolomide.

Patients will be randomised to either the HSV1716 treatment group or the chemotherapy treatment group:

HSV1716 group:
treatment with intratumoural administration of HSV1716 with the potential to repeat at six-weekly intervals based on clinical condition and/or tumour status on imaging.

Chemotherapy group:
treatment with conventional (PCV) chemotherapy in six-weekly cycles.

6. I have a patient who might be suitable for an ongoing trial. Which sites take part in the trial? Whom do I contact for more information?

Information on the clinical trials can be obtained by contacting Jennifer Stewart on 0870 1716 00.