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CHAPTER THIRTY-TWO

LATEST TRIAL FAILS


BOSTON, MA—Hopes for a cure to canine facial tumor disease (CFTD) were dashed last week by the announcement that a promising immunotherapeutic agent failed in animal trials.

Canizumab, developed by the animal health division of Bingham Pharmaceuticals, had shown the most potential of any therapy tried so far.

CFTD’s sudden appearance and unusual properties have baffled scientists. While population-scale epidemics have been documented in other species—including a similar transmissible tumor disease in the Tasmanian Devil population of New Zealand—natural or acquired resistance typically allows a subset of the population to survive. No such resistance has yet emerged among canines.

One reason CFTD has proven so difficult to treat is that the tumor cells hide themselves from the immune system of an infected dog. Normal healthy cells produce a protein, called MHC, that helps the body distinguish its own cells from invasive pathogens or unhealthy cells, such as tumors. Early investigations of the tumors of infected dogs, however, revealed that the cancer cells do not produce MHC.

“MHC proteins help the immune system distinguish between a dog’s own healthy cells and invading or infected ones,” said Dr. Ellen Marley, a cancer immunologist at Johns Hopkins University who was not involved with the trial. “By not producing them, CFTD renders itself invisible to one of the body’s best avenues of defense.”

Early on in the epidemic, scientists sequenced the genome of CFTD tumor cells and found that they harbored thousands of DNA mutations—far more than most human tumors. Strikingly, many of the mutations were shared across all tumors. They disrupted genes that normally helped dogs fight infections, recognize unhealthy cells, and remove them. The pattern of shared mutations is unusual and led scientists to believe that the tumors might somehow be transmissible from one dog to another. Subsequent investigations uncovered evidence that this was, at least in some part, true. Most cases of CFTD emerge after contact with an infected dog. Because the tumors are initially small, many owners did not realize their dogs were infected until they had spread it to other animals. Worse, there appears to be a latent means of environmental infection for some dogs. A sidewalk or dog park visited by a single infected animal can give rise to new cases days or weeks later.

Many researchers believe that immunosuppression by the tumor cells is key to their survival (and the host animal’s demise). Canizumab, by targeting this mechanism, was expected to help a dog’s immune system clear the tumor cells before they took hold. The drug passed initial safety trials late last year.

“Canuzimab targets two therapeutic mechanisms simultaneously,” said Dr. Jonathan Fisker, senior scientist at Bingham Pharmaceuticals, after the conclusion of the initial safety trials. “First, it inhibits the immune cell checkpoint that tumors leverage to evade T cells. Second, it boosts the immunogenicity of tumor cells to make them better targets for immune elimination.”

A phase II trial began almost immediately to prove efficacy. This is where it seems that the drug’s performance saw some challenges. Though it was well-tolerated by infected and healthy dogs alike, the drug failed to stop the relentless onslaught of CFTD. There was no significance difference in survival or tumor burden between dogs that got Canuzimab and ones that received the placebo. The announcement of the trial’s failure sent biotechnology stocks tumbling on Thursday.

The outcome is not only disappointing for investors, but also for the millions of dog lovers around the world who hoped Canuzimab would bring our furry companions back. Worse, the high-profile failure makes it even less likely that other biotechnology firms will invest in new CFTD research in the near future.



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Framed