Developing New Treatments for Cancers

Oncolytic adenoviruses, an experimental cancer treatment may, with further research become a very effective weapon in the battle against some forms of aggressive cancer, says the Trastuzucrad project’s group leader Akseli Hemminki, of the Finnish Cancer Institute.

Cancer devastates lives – merely a diagnosis of it can cause huge disruption and trauma to a patient. The Trastuzucrad project, based in at the University of Helsinki, Finland, has been looking at four types of cancer – breast, ovarian, gastric and esophageal – to see if oncolytic adenoviruses expressing trastuzumab, a monoclonal antibody, will exhibit improved anticancer effects when compared to virus or antibody treatment alone. Oncolytic adenoviruses, an experimental form of cancer treatment, have undergone lab studies with many different tumour types, as well as data from clinical trials suggesting that treatments are safe, well tolerated, and can be effective in some patients.

However, it’s become clear is that the efficacy of first generation viruses would benefit from enhancement. Despite recent advances, chemotherapy provides only a modest increase in survival for these types of cancers, often with significant side effects. Therefore, new treatments are needed for all four tumor types. Recently, Her2 amplification has been found common in both tumour types, which has resulted in initiation of clinical trials evaluating trastuzumab in patients with metastatic Her2+ disease. Trastuzumab is a monoclonal antibody against Her2, which is a classic tumour-associated molecule. Antibodies are molecules normally produced by the body in response to infection or foreign molecules. Antibodies ‘point out bad substances’ to immunological cells and other molecules of the body, which then attempt to eradicate the ‘bad substances’. ‘Monoclonal antibody’ indicates a synthetic molecule engineered in the lab to identify targets not normally recognised as ‘bad’.

In the case of trastuzumab, the antibody recognises Her2, which is not normally recognized by the body as bad even though it is highly expressed by tumors and has a role in tumor aggressiveness. Trastuzumab helps in this recognition and also interferes with Her2 signalling and thus it has many useful anti-tumour features. Although usually well-tolerated, trastuzumab has common side effects including immune and pulmonary reactions, anaphylaxis and even the serious cardiomyopathy. Local production of trastuzumab could reduce systemic exposure, which causes side effects.

The project hypothesis then, is that the construction of oncolytic adenoviruses will result in production of high, sustained concentrations of functional trastuzumab in cancer cell lines and in tumours.

The antitumour activity of trastuzumab could be harnessed into a safe and inexpensive vehicle, which might be promising for clinical testing. Theoretically, a single injection of oncolytic adenovirus coding for trastuzumab could replace repeated intravenous administration, which would save on treatment-associated costs as well as freeing the patient from frequent hospital visits. Long lasting, in situ antibody production by the proposed adenoviruses could solve the common problems of monoclonal antibodies as low bioavailability and adverse effects because of systemic, high dose administrations. The viruses’ combined anticancer effect, of capsid modified oncolytic adenoviruses with efficient trastuzumab treatment, might result in additive or synergistic antitumour efficacy.

“When trastuzumab is given intravenously, it has equal concentrations at ‘non-target’ normal tissues and at ‘target’ tumour tissues,” explains Trastuzucrad group leader Akseli Hemminki. “The concentration in normal tissues can cause side effects, which limits the dose that can be given. Although Her2 is expressed to a high degree in many tumours, normal hearts can also expresses some Her2 and it is known that high trastuzumab concentrations can cause damage to the heart. By producing trastuzumab locally at the tumour, we can achieve high concentrations where it counts, while minimising systemic concentrations and associated side effects.

“We have managed to construct some of the viruses identified in the study plan and in vitro testing seems to indicate that the approach is working. Ultimately, the discoveries we make in the project might lead to testing of the approach in clinical trials. Also, our research might aid in understanding tumour immunology better than before. Additionally, oncolytic viruses as drug delivery vehicles (for tumour specific drug production) might be an important field in the future.”

The research project has collaborated globally with other teams investigating oncolytic viruses. For example, during a backup strategy to utilise oncolytic vaccinia virus a close collaboration with John Bell (Ottawa) helped to set up a vaccinia programme in the lab which was able to achieve production of various transgenes from infected cells. All data will be reported at international meetings and in peer-reviewed international journals, and it is hoped many researchers will gain from their results.

Hemminki understands that the road is long – new regulations mean that European clinical trials are expensive, so most new drugs are developed in Asia and the USA – but hopes that the approach could eventually provoke clinical trials.

For more information on the project, contact Akseli Hemminki at akseli.hemminki@helsinki.fi

Published: Thursday, 22nd April 2010 by Tom Freeman

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