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Conditionally replicating viruses have been used clinically for many years, contributing to global health care goals such as the eradication of small pox. We and others are now proposing that conditionally replicating viruses could also be useful for the treatment of cancer, by designing or selecting viruses that are dependent on a malignant phenotype. Early clinical trials with conditionally replicating adenovirus (and other viruses) have shown the approach to be safe and there have been encouraging signs of tumour responses. However, the results also indicated that the viruses tested so far are incompatible with systemic delivery and incapable of efficient spread within large tumour masses. This limits the use of the oncolytic approach to multiple injections in isolated, non metastatic nodules. To improve anti-cancer efficacy Hybrid Systems have identified, by a process of bio-selection, a group B derived adenovirus that has a greater capacity to spread in tumour tissue while maintaining the tumour selectivity. The virus also has improved serum stability and may be effective by systemic administration for some tumour indications. The disadvantage of generating a virus with an optimal therapeutic phenotype (rapid replication and spread in vivo) is that yields in vitro are low when established manufacturing production protocols are used. Specifically, optimised therapeutic viruses are released from cells into the supernatant very early after initial infection. Although this is beneficial for a rolling infection through tumours, it is not optimal for a 'batch growth' method where viruses are amplified and harvested from inside cells. In order to develop methods for the production of adenoviruses with a rapid spread phenotype we first need to understand and control the process of early release or develop technologies for purifying virus from the supernatant. This proposal will include novel methods of controlling virus propagation and new techniques for virus purification including asymmetric flow field flow fractionation (AF4). The purposes of this project will be to generate a scalable, cGMP compliant manufacturing process that maximises the yield of early-lytic adenoviruses from the supernatant and rapidly progresses this novel virus in to clinical trials. It may also be possible to apply the same process to other types of adenovirus for GMP manufacture. This research will be undertaken in collaboration with Prof Seymour's research group at the University of Oxford, and through him will involve expert input from the University's cGMP adenovirus manufacturing unit, the Clinical Bio-manufacturing Facility.

The greatest challenge in oncological drug delivery is achieving successful penetration and distribution of the therapeutic agent throughout the tumour: billions of pounds have been spent to date in deploying biochemical approaches in an attempt to solve what is essentially an engineering problem, namely the transport of therapeutics from the blood stream to reach every cancer cell. OxCD3 will seek to transform both clinical and industry practice in drug delivery by demonstrating the value and feasibility of engineering approaches, involving a combination of stimulus-responsive nanocarriers and medical devices already in clinical use, for improved tumour uptake and therapeutic outcome. The Programme Grant will enable the creation of a sustainable, world-unique multi-disciplinary environment for combinational engineering of biology, chemistry and medical devices to improve drug delivery under a single roof. It is also expected to create a unique training environment for the next generation of young scientists working on combination therapies and biomedical nanotechnology, by providing direct exposure to regulatory and manufacturing issues encountered when translating laboratory research into production and clinical practice. A unique feature of the Centre is the capability to design both devices and drug delivery vehicles under a single roof. In the first 5 years, under EPSRC funding, up to 3 carefully selected "Device+Drug" exemplars will be manufactured to GMP, ready for Phase I clinical trials, to provide compelling evidence of feasibility to industrial partners and clinicians; in the next 5 years, a private-public partnership will be built to complete clinical trials of these exemplars using therapeutics of strategic significance to the pharmaceutical industry; beyond 10 years, full industrial sponsorship of the OXCD3 is anticipated, which will focus on addressing next-generation challenges in drug delivery (beyond cancer) in partnership with industry and clinicians. The transformative aim over 50 years is to position the UK as the world leader for multi-disciplinary drug delivery development, complementing its existing position as a drug discovery leader, from design to manufacture and clinical trials.