Tuesday, January 19, 2016

interesting article about new targeted cancer therapies in yesterday newspaper

STAFF WRITER

POSTED: Sunday, January 17, 2016, 8:51 AM


When President Obama announced his "precision medicine" initiative a year ago, the White House spotlighted Emily Whitehead as an example of patients who have already benefited from an approach most people have never heard of. The central Pennsylvania girl, now 10, was near death in 2012 when researchers at Children's Hospital of Philadelphia engineered her own immune system's T cells to recognize and attack her leukemia cells.

Though Emily's therapy was custom made, it didn't take into account individual differences in her genetic makeup, lifestyle, or environment - which is how the president's initiative and the National Institutes of Health define precision medicine.

Little wonder, then, that there is confusion over just what this phrase means.
"The definition of precision medicine is in the eye of the beholder," acknowledged Children's Hospital oncologist Stephan Grupp, who treated Emily.  "For me, precision medicine is about trying to go after a tumor a lot more specifically. Chemotherapy is as imprecise as it gets - somewhere between a bomb and a shotgun."

Grupp will be a speaker at Cancer Precision Medicine, Big Ideas in Research, Treatment and Prevention, a half-day public conference Thursday presented by The Inquirer and the American Association for Cancer Research. Directors of six Pennsylvania cancer centers will offer their perspectives on the promise of precision cancer medicine and answer / questions from the audience.

Despite its name, precision medicine covers a lot of imprecise ground. In that regard, it is much like an earlier incarnation, so-called personalized medicine - a field that even has a five-year-old scholarly journal. Considerable vagueness and hype surround these concepts and terminology. Still, precision medicine is emblematic of a revolution underway in health care, particularly oncology. The transformation reflects the convergence of three things: molecular technologies that can decipher and manipulate basic cellular interactions; the advent of rapid, lower-cost DNA sequencing methods; and computer platforms that can crunch vast amounts of data.  "Precision medicine addresses the unique characteristics of patients at the level of their genes and metabolism in a way that hasn't been done historically in medicine," said Lankenau Institute president and CEO George C. Prendergast, who will be a panelist at the conference.

Of course, some types of genetic assessment are already standard in modern health care. Think of prenatal testing for Down syndrome, and newborn testing for inherited disorders such as cystic fibrosis and sickle cell disease. But only in oncology have both diagnosis and treatment become increasingly personalized and precise.

Why cancer instead of, say, diabetes or heart disease?   "A lot of conceptual and molecular advances were pioneered in cancer," Prendergast said. "The genetic revolution has had the most influence in cancer."

More than other diseases, cancer is the result of cumulative, continual genetic defects that turn the body's own cells into rogues and then keep the immune system from killing them.   Conventional oncology weapons that cut out or kill cancer cells - surgery, chemotherapy, and radiation - are effective, but they involve collateral damage to healthy tissue. And when cancer metastasizes, such blunt weapons can't stop it.

The mid-1970s brought several breakthroughs in the search for ways to marshal the immune system against cancer. Scientists discovered interleukin 2, which has direct effects on disease-fighting T cells. They also developed monoclonal antibodies, genetically engineered proteins that target an identifying marker, or antigen, on tumor cells, then deliver a deadly blow. Today, "targeted" therapies such as Avastin and Gleevec - drugs that disrupt specific molecules involved in the growth and spread of cancer - have become the backbone of oncology. More than 50 such drugs have been approved, with sales rising from 11 percent of the global oncology market in 2003 to 48 percent in 2014, according to the market research firm IMS Health. And although targeted drugs are not yet available for most patients, these medicines accounted for the majority of the 45 new cancer drugs launched between 2010 and 2014, IMS found.
Increasingly, such therapies are approved for use with molecular diagnostic tests to identify patients who have the relevant target. Although that adds to the complexity and cost of treatment,  it also offers reprieves to patients like Albert Snite, 67, of Philadelphia.

Last January, when the retired Common Pleas Court judge was diagnosed with lung cancer that had spread to his brain, his genetic tests at the University of Pennsylvania found no targetable mutation. He was treated with radiation and chemotherapy.  But over the summer, researchers announced the discovery of a new target - a mutation involved in malignant-  cell migration and invasion - for crizotinib, a metastatic lung cancer drug  approved in 2013. Shortly afterward, as Snite's lung tumor progressed, his doctors reviewed his test results and realized he had the newly identified mutation.  "I started crizotinib in September. I had one scan after six weeks. My lungs looked significantly better. And I feel good! It is truly amazing," Snite said, adding that another scan this  month was unchanged.

Even targeted therapies are not magic bullets. Patients who respond - and not all do - often see their cancers develop resistance. The good news, however, is that efforts to harness the immune system in novel ways are yielding successes. Witness patients like Emily Whitehead, who remains cancer-free.  Three main "immunotherapy" approaches have worked to varying degrees - and with varying toxic side effects:  Bioengineered T cells: T cells, the soldiers of the immune system, are removed from the patient's own blood, genetically rigged to recognize and attack a cancer cell antigen, the  grown into the billions and put back in the patient. Penn, CHOP, the National Cancer Institute, and other centers have achieved high rates of long-lasting remissions of certain blood cancers, but this approach has yet to work for solid-tumor cancers. Penn's therapy often has severe but manageable toxicity. Because of the complexity and cost of this approach, it won't be widely used, some experts believe.

Therapeutic vaccines: Unlike preventive vaccines, which preset the immune system to recognize and kill infectious invaders, treatment vaccines are designed to provoke a
heightened immune response to cancer cell antigens. In 2010, Provenge for prostate cancer became the only approved therapeutic vaccine, but it was costly to customize and barely effective; maker Dendreon filed for bankruptcy last year. Still, this technique is improving. For example, two Penn scientists - Yvonne Paterson and David B. Weiner - each developed  novel vaccine technology that separate biotech firms have licensed and are using in clinical trials for cervical and other cancers.

Overcome immune tolerance: Instead of directly revving up the immune response, this approach interferes with one of cancer's main defenses - its ability to evade and suppress the immune system. Since 2011, three "checkpoint inhibitors" have been approved for advanced melanoma and lung and kidney cancers. These drugs and even newer versions are being tested in cancers of the pancreas, colon, brain, and other organs. Prendergast, at Lankenau, has been a leader in research of an enzyme pathway called IDO (for indoleamine 2,3-dioxygenase) that cancer uses not only to escape immune detection, but to attract a blood supply and metastasize."The field has stressed how to activate the immune system," Prendergast said. "In the last 10 years, we realized the tumor is standing on the brakes of the immune system. We have to  take off the brakes. That was one of the shocks of my career."    Some people have immune systems that are inherently superior at unmasking and managing dangerous cells. That's why most smokers don't get lung cancer and many old men have   prostate cancer that will never harm them.  "The problem is not that there are rogue cells in the body, but that the body is mismanaging them," Prendergast said.

Figuring out why is part of precision medicine.    "You can match a blood transfusion to a blood type - that was an important discovery," Obama said a year ago. "What if matching a cancer cure to our genetic code was just as easy, just as standard?


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