The body doesn't process drugs in the same way throughout the day

It’s news to no one that your body works differently when you’re awake and when you’re sleeping. But could the different states also affect how your body processes certain life-saving drugs? Researchers, reporting Friday in the journal Nature Communications, found that when it comes to cancer drugs, the answer may be yes.
Researchers at the Weizmann Institute of Science discovered—by happy accident—that some of the body’s molecular functions during the day may interfere with the effectiveness of certain cancer medication. Specifically, they found that the normal day-time production of some steroid hormones in the body actually inhibited the work of epidermal growth factor (EGF) receptors—which are the proteins targeted by a class of anti-cancer drugs. Tumor cells plant these receptors on their surfaces to attract nutrients that help them survive and grow. Drugs, including the breast cancer agent lapatinib, can block these receptors on tumors, and such medications are a popular way to treat breast cancers expressing epidermal growth factor.
But Yosef Yarden, a professor in the department of biological regulation, and his team found that when the tumor cells simultaneously bind to something else—such as steroid hormones—the EGF receptors are less active, making drugs like lapatinib less potent.
The findings are still preliminary, but there is other evidence that the day-night cycle may be a potentially important factor in determining cancer treatment dosing in coming years. Some studies showed, for example, that when the 24-hour rest and activity cycle is broken metabolically, and the EGF receptors aren’t given enough time to be active, certain tumors in animals grow two to three times faster.

Why Cancer Drugs May Work Better While You Sleep

The combination, he says, may be more effective since one drug works to suss out tumor cells, like shining a molecular spotlight on them, while the other builds up the body’s defenses against them, allowing immune cells to better target and eliminate cancers.
The time that both groups of patients enjoyed before their melanoma recurred, however, was similar. But Hodi and his team note that the inflammation caused as a side effect of the drugs could be interpreted as early tumor sites, leading researchers to record the presence of tumors that may not be there.
Teasing apart that issue and determining the safe and optimal doses of the combination will require more studies, says Hodi. The dose of ipilimumab he used, for example, was higher than the one approved by the FDA in 2011, since this study was begun before the agency approved the drug. But the idea that a combination of powerful immune-based drugs could help cancer patients fight their disease and survive longer is encouraging. “This world of [new cancer treatments] is moving fast, and there are a slew of possible combinations that others are studying now,” he says. “It’s where the future of cancer therapy will be.”

Promising New Cancer Treatment Uses Immune Cells

Cancer researchers are pumping out study after study trying to figure out how best to use the body’s own immune system to fight cancer tumors.
Scientists led by Dr. F. Stephen Hodi at Dana Farber Cancer Institute show for the first time that combining two drugs that target the immune system in different ways could help melanoma patients survive longer. From 2010 to 2011, 245 patients with advanced skin cancer who had not responded to at least one previous treatment were randomly assigned to get a newly approved drug, ipilimumab, designed to help the immune system better target tumors, either alone or in combination with another drug. Ipilimumab (marketed as Yervoy), was among the first anti-cancer medications that allows immune cells to “see” tumors better; since tumors grow from originally normal cells, the immune system often gives them a pass and doesn’t attack them as foreign. But drugs like ipilimumab, called checkpoint blockade inhibitors, help immune cells to look past cancer’s disguise and target abnormally growing tumors.
In the study, those who received the combination of ipilimumab and sargramostim, another drug that gives the immune system a laser-like focus on the proteins found on tumors, survived an average of 17.5 months after the study began, compared to 12.7 months for those who took ipilimumab alone. At the end of a year, nearly 70% of those receiving the combination were alive, while 53% of those in the ipilimumab alone group were.
“We show that the combination improves survival, and at the same time decreases side effects,” says Hodi. The patients receiving the two drugs reported fewer gut and respiratory complications, two of the organ systems most affected by checkpoint inhibitor drugs like ipilimumab.

Scalability and cost,Pfizer's reason for different approach

“We would like to take it to the next level, where CAR therapies become a more standardized, highly controlled treatment,” said Mikael Dolsten, Pfizer’s head of global research and development.

Working with French biotech Cellectis SA, ALCLS.FR -2.65% Pfizer wants to develop a generic CAR therapy for use in any patient, potentially lowering its cost. But its research is still preclinical, and may not work in humans.

Stephen McGarry, global head of health-care research at Société Générale, agrees the treatments being developed by Novartis and Juno could justify “astronomical” prices, although he thinks health-care payers and patients might fight back.

“When you look at the initial data with the Novartis therapy, you’re getting cures in some kids—what do you charge for that?” he asks

Juno-backed Sloan-Kettering trial, recruiting patients!

There are still big unanswered questions about CAR therapies: one is how long they last.

That is hard to tell because of the small numbers of patients treated so far, and because many of those whose cancer went into remission after the CAR therapies subsequently became eligible for stem-cell transplants which can themselves prolong survival.

Another concern is a potentially dangerous side effect called “cytokine-release syndrome,” an immune response which shows the therapy is working, but which can cause a sharp drop in blood pressure and surge in the heart rate.

The deaths of two patients in a Juno-backed Sloan-Kettering trial in March caused a temporary halt in the study because of worries over these immune responses.

“Patients need to be healthy enough to combat that side effect,” says Mr. Bishop, who thinks it is now manageable. The trial is recruiting patients again, excluding those with a risk of heart failure, and giving those with very advanced leukemia fewer modified cells.

New Costly Cancer Treatments Face Hurdles Getting to Patients

But the biggest hurdle yet may be the cost of the therapies.

The genetic engineering involved means CAR therapies are very complex to manufacture, and each is a unique personalized treatment using a patient’s own blood cells. The inability to mass-produce them has likely implications for how much companies will charge for them.

“What we’re talking about here is a single, very expensive therapy that’s used once for a specific patient and is not generalizable,” says Dr. Malcolm Brenner, director of the Center for Cell and Gene Therapy at the Texas Children’s Hospital in Houston.

Dr. Brenner signed a deal in March to commercialize his own CAR research with Celgene.

Novartis and Juno say it is too early to speculate on price, although Dr. Usman agrees the challenge is getting the manufacturing process to “a viable level where it’s both affordable and attractive.”

While most analysts think it is too early to estimate potential revenue or price, Citigroup believes CAR therapies could cost in excess of $500,000 per patient, which it notes is roughly in line with the cost of a stem cell transplant.

“This technology needs to be widely developed and accessible to patients,” says Dr. DeAngelo. “If the cost is going to be a hindrance, it’s going to be a really sad day.”

Novartis, Juno Conduct New Studies on Leukemia Therapies

Cancer treatments that genetically modify patients’ blood cells to target the disease have shown amazing results in clinical trials. Now drug companies and biotechs must overcome big hurdles to get them into hospitals, including their potential cost.

In two separate clinical trials—sponsored by Novartis AG NOVN.VX -0.51% of Switzerland and Seattle-based biotech Juno Therapeutics Inc.—almost 90% of patients saw their leukemia disappear after being given experimental so-called CAR T-cell therapies. The results were published in December and February, respectively.

Both trials were in small numbers of patients: 22 children in the Novartis trial and 16 adults in the Juno trial. The patients had acute lymphoblastic leukemia—the most common childhood cancer—and had exhausted standard treatments. Both companies are now conducting larger trials.

“CAR T cells are probably one of the most exciting concepts and fields to come out in cancer in a very, very long time,” says Dr. Daniel DeAngelo, a Boston-based hematologist and associate professor of medicine at Harvard Medical School, who wasn’t involved in either study.

Usman Azam, head of cell and gene therapies at Novartis, calls the therapies “critically important” for Novartis. “I think that a cure for cancers such as leukemia and lymphoma through a CAR technology is plausible,” said Dr. Azam in an interview with The Wall Street Journal. “Our job is to get this into patients as soon as we feasibly can.”