Measles virus: from bad cop to cancer cure?

If you’re asked to think of measles, you’ll doubtless think of negative connotations. It’s true; measles virus suffers a bad press. Most likely you’ll think of a nasty virus that causes illness and an unpleasant rash.  There’s a strong possibility you’ll think of recent outbreaks in South Wales, debates over MMR and autism, and discredited research by a certain Dr Andrew Wakefield.  However, and say this quietly, it seems measles is about to turn good guy.

The good press began with a bang earlier in 2014.  Pioneering earlier research from the group lead Stephen Russell explored the measles virus for its therapeutic potential in fighting cancer (Li et al.).  Using a measles strain that had been genetically manipulated and “tamed” (or “attenuated”), their research progressed from promising pre-clinical observations in animal models into clinical trials.  In May 2014, the first clinical data was released suggesting that intravenous administration of high doses of this virus (approx. 10,000 times the amount in a vaccine) reduced or eliminated tumours in two patients suffering multiple metastatic myelomas. One patient (a 49-year-old woman) responded particularly well; other than one local relapse that was treated with radiotherapy, her tumours disappeared and cancer has remained in remission for over six months (Russell et al.).

In this month’s edition of Molecular Therapy (November 2014), Engeland et al., sought to generate new, more potent cancer fighting versions of measles viruses. When viruses replicate in tumour cells, they kill the infected cancer cells directly causing them to burst releasing free virus that goes on to infect (and kill) surrounding cancer cells. In addition, proteins from within the cancer cells are released when the cells burst and recognised as cancerous by the immune system. This “primes” immune cells (T-cells) to also attack and kill remaining cancer cells. With time, this anti-tumour immune response becomes dampened by proteins called CTLA-4 and PD-1/PD-L1. Fortunately, antibodies targeting these proteins (e.g. Ipilimumab, or Yervoy™ which targets CTLA-4) can prevent their function so allowing T-cells to continue killing cancer cells.

Elegantly, Engeland et al., produced a genetically engineered measles virus targeted to cancer cells that also produced antibodies that bind and block the effects of CTLA-4 and PD-L1. This virus therefore combined the direct effect of replicating virus killing cancer cells by causing the cells to burst (oncolysis) with the indirect effect of promoting T-cell killing of cancer cells (immunotherapy) by preventing dampening of the anti-tumour immune response.

Engeland et al., demonstrated, with human tumours grown in immune deficient mice, that their newly engineered measles virus was as effective at oncolysis as a control measles virus that did not produce antibodies. In order to grow human tumours in mice it is vital that the mice are immune deficient to prevent “rejection” of the foreign cells. The authors therefore describe a new cancer model with an intact immune system.  Using this model, the authors were able to demonstrate significant additional benefits, in terms of survival and tumour growth rates, when treating animals with their new viruses expressing antibodies targeting CTLA-4 and PD-L1 versus measles virus not expressing antibodies.

Just as man domesticated the wolf into “man’s best friend”, are we on the verge of a new era of domesticating nature’s bad cop viruses into “cancer’s worst enemy”?  Time will tell, but one thing is for sure – the future looks bright for measles virus.

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References

Engeland, C.E, Grossardt, C., et al. (2014). CTLA-4 and PD-L1 Checkpoint Blockade Enhances Oncolytic Measles Virus Therapy. Molecular Therapy. 22(11): 1949-1959.

Li, H., Peng, K.W., et al. (2010). Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy. Cancer Gene Therapy. 17(8): 550-558.

Russell, S.J., Federspiel M.J., et al. (2014). Remission of disseminated cancer after systemic oncolytic virotherapy. Mayo Clinic Proceedings. 89(7): 926-933.

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