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Thursday, December 29, 2016
Nanodiscs target tumors in potential cancer vaccine
Nanodiscs may be used in a vaccine against some types of cancer, with a new study finding the technology effective in killing and preventing recurrence of tumors(Credit:lightsource/Depositphotos)
Colon and melanoma cancers could soon be treated with a simple vaccine, if research from the University of Michigan lives up to its early promise. Using synthetic nanodiscs, scientists were able to train the immune systems of mice to better target cancerous cells, killing tumors within 10 days and preventing them from reappearing even months after treatment.
The technique works like any other vaccine: a small amount of biomarkers of the target disease are introduced into the body, which the immune system will rally against to build its defenses. In this case, those markers come in the form of tumor neoantigens that were packed onto nanodiscs measuring just 10 nanometers wide and made of high-density lipoproteins.
"We are basically educating the immune system with these nanodiscs so that immune cells can attack cancer cells in a personalized manner," says James Moon, an author of the study.
Tested in mice with existing colon and melanoma tumors, 27 percent of the mice's T cells were found to turn their attention to the cancer cells. In conjunction with their vaccine, the team used "immune checkpoint inhibitors," drugs that target certain proteins like PD-1 in order to keep T cells healthy and fighting. With both systems working together, most of the tumors vanished within 10 days, and when the researchers tried to reintroduce the tumor cells 70 days later, the test subjects' immune systems didn't give them a chance to grow.
"This suggests the immune system 'remembered' the cancer cells for long-term immunity," says Rui Kuai, lead author of the study.
Buoyed by these results, the researchers plan to increase the sample size of their vaccine, and see how it fares in animals larger than mice.
"The holy grail in cancer immunotherapy is to eradicate tumors and prevent future recurrence without systemic toxicity, and our studies have produced very promising results in mice," says Moon.
Celine Ryan at her home in Rochester Hills, Mich., this week. She is now cancer-free after immunotherapy treatment.CreditLaura McDermott for The New York Times
The remarkable recovery of a woman with advanced colon cancer, after treatment with cells from her own immune system, may lead to new options for thousands of other patients with colon or pancreatic cancer, researchers are reporting.
Her treatment was the first to successfully target a common cancer mutation that scientists have tried to attack for decades. Until now, that mutation has been bulletproof, so resistant to every attempt at treatment that scientists have described it as “undruggable.”
An article about the case, from a team led by Dr. Steven A. Rosenberg, chief of surgery at the National Cancer Institute, was published on Wednesday in The New England Journal of Medicine.
The patient, Celine Ryan, 50, an engineer, database programmer and the mother of five, has an unusual genetic makeup that allowed the treatment to work. She is now cancer-free, though not considered cured.
The treatment was a form of immunotherapy, which enlists a patient’s immune system to fight disease. The field is revolutionizing cancer treatment.
An experiment on one patient cannot determine whether a treatment will be effective in others, but doctors said the results had the potential to help more people.
“It has huge implications,” Dr. Carl H. June, from the University of Pennsylvania, said in an interview. He was not part of the study, but wrote an editorial accompanying it in the journal.
Dr. June said the research was the first successful targeting of a defect in a gene called KRAS, and is important because mutations in the gene are so common. “Every single pancreatic cancer patient has KRAS,” Dr. June said, adding that the pharmaceutical industry has spent billions trying unsuccessfully to target KRAS.
Still, he said, the big question is whether this case is “one in a million, or something that can be replicated and built upon?”
About 53,000 cases of pancreatic cancer are expected in the United Statesthis year, and nearly 42,000 deaths. It is one of the deadliest cancers; fewer than 10 percent of patients survive five years. Worldwide, it killed about 330,000 people in 2012, the most recent year with global statisticsavailable.
Cell Wars
Articles in this series are exploring the novel uses of immunotherapy to combat cancer.
From 30 to 50 percent of colorectal cancers have KRAS mutations, too, and about 13 percent have the same mutation that Ms. Ryan has. In the United States, about 95,000 cases of colon cancer and 39,000 cases of rectal cancer are expected in 2016, and 49,000 deaths from the two forms combined. Globally, there were 1.4 million cases and 694,000 deaths in 2012.
The new discovery might not have been made — at least, not now — without Ms. Ryan’s persistence. Researchers twice denied her request to enter the clinical trial, saying her tumors were not large enough, she said. But she refused to give up and was finally let in.
The research involves cancer-fighting immune cells called tumor-infiltrating lymphocytes, or TILs. These are white blood cells that swarm around tumors, a sign that the immune system is trying to attack the cancer. Dr. Rosenberg has been studying TILs for decades, with the goal of enhancing their ability to fight the disease and using them as a treatment.
An attempt to treat another patient with tumors much like Ms. Ryan’s did not work, almost certainly because the researchers could not produce enough highly targeted TILs, Dr. Rosenberg said.
So far, the cells have worked best against advanced melanoma, a deadly form of skin cancer. By extracting TILs from tumors, multiplying them in the lab and then returning them to the patient, Dr. Rosenberg’s team has produced long remissions in 20 to 25 percent of patients with that disease.
More recently, the team has focused on an even tougher problem: tumors in the digestive system, including the colon and pancreas, and in ovaries, breasts and other organs, which cause more than 80 percent of the 596,000 cancer deaths in the United States each year.
The researchers analyze tumors for mutations — genetic flaws that set the cancer cells apart from normal ones. They also study TILs, looking for immune cells that can recognize mutations and therefore attack cancerous cells but leave healthy ones alone.
Ms. Ryan, from Rochester Hills, Mich., had colon cancer that spread to her lungs despite surgery, chemotherapy and radiation. With few options, she began looking into research programs and came across the TILs research at the National Cancer Institute. In December 2014, she called the institute, hoping to join the study.
But she was told, based on her scans and records, that she did not have a tumor big enough to yield TILs. A research nurse suggested she send her next set of scans; maybe, in the interim, the tumors would grow. Ms. Ryan took that advice — and was devastated to be turned down again.
“I felt sure I’d get in,” Ms. Ryan said. “My heart sank.”
The rejection left her sobbing. But then she and her husband pulled up images of her scans on their home computer, took screen shots and measurements of a lung tumor that seemed to match the study criteria, and sent them to the cancer institute. She included a polite note asking that, if her tumor was not eligible, she be told why.
“I was trying not to sound like a desperate maniac, but I was a desperate maniac,” she said.
In March 2015, she got in. Whether the screen shots were a deciding factor is not clear. Dr. Rosenberg said the team had been watching her progress and brought her in as soon as they identified operable tumors.
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A month later, the researchers performed surgery, removing several lung tumors to search for TILs.
Ms. Ryan’s tissue turned out to be a medical gold mine. She had a KRAS mutation and her TILs included killer T-cells that locked onto the mutation like guided missiles.
Her T-cells were able to recognize the mutation because she has an uncommon tissue type, which is a genetically determined trait. As a result, she carries a certain protein on the surface of her cells that plays an essential role in displaying the KRAS mutation so that cancer-killing cells can find it and attack.
Best of all, from a scientific standpoint, was that Ms. Ryan’s KRAS mutation is shared by many other patients with colon and pancreatic cancers. Those who share her tissue type may also be good candidates for treatment with TILs.
Researchers say they now have a blueprint that may enable them to develop cell treatments for other patients as well. The killer T-cells have surface molecules called receptors that lock onto mutated cells, and it may be possible to genetically engineer patients’ T-cells to give them those receptors and their cancer-targeting ability.
To treat Ms. Ryan, the team selected a culture of TILs with high levels of immune cells that specifically attacked her mutation. They multiplied those cells in the laboratory to produce huge numbers.
Ms. Ryan was first given chemotherapy to wipe out most of her white blood cells and allow the TILs to flourish. Then, more than 100 billion TILs were dripped into her bloodstream through an intravenous line; it took about 20 minutes, she said. About 75 percent were the killer T-cells that targeted her mutation. She was also given interleukin-2, a substance that stimulates killer T-cells.
Before being treated, Ms. Ryan had seven tumors in her lungs. Over the next nine months, six shrank and then disappeared. The seventh shrank at first, but then progressed. To remove it, surgeons took out the lower lobe of her left lung.
Tests of the excised tumor explained why it had resisted treatment: It had mutated and no longer carried the tissue-type marker that had enabled the T-cells to attack it.
The tumor’s ability to escape the T-cells reveals a potential weak spot in the approach of targeting a single mutation, said Dr. Drew M. Pardoll, the director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins University School of Medicine. Calling cancer “versatile,” he said, “The tumor always seems to come up with a workaround.”
Even so, he said the research was “a real and solid step forward.”
Today, Ms. Ryan has no signs of cancer.
“I feel great,” she said.
But recently, two friends died of colon cancer, she said, adding, “I so hope they can get this treatment to everybody who needs it, and that it works.”
Denise Albert, the co-founder of The MOMS, is speaking out after what she calls an “horrific” pat down from Transportation Security Administration (TSA) agents at the Los Angeles International Airport on Sunday — all over medication related to her breast cancer treatment.
Albert, who is a frequent guest on PIX11 Morning News, told the outlet that she was traveling through security when she was pulled aside by agents for a manual search. The cause for further search was a medical cream she had packed in her carry on luggage, Albert told PIX11.
Albert wrote on The MOMS website that the medical cream is not usually an issue and she’s been granted approval to carry it on other flights. She also noted that she made the agents aware of the medication and her medical port before the patdown.
“I don’t know what was different this time but TSA agents aggressively attempted to do a body cavity search in public,” said Albert in the post. “I was TSA precheck and once through the scanner they asked me to take off my shoes. I explained I didn’t have socks on and that my cream is for an infection from my current treatment, including on my feet.”
According to Albert, the TSA agents told her they needed to perform a full body pat down, using “as much pressure” as necessary.
She was forced to remove her wig, and remained barefoot for at least 20 minutes during the ordeal.
“I told them my feet were freezing,” Albert wrote online. “Also a side effect from chemo. They refused to help me. The woman reached behind me and forceable and aggressively put her hands down my jeans in the back.”
She explained, “When I kept asking why they needed to do all of this, they kept saying because I wanted to bring medical cream on the plane.”
The entire incident was caught on camera, and only ended when a supervisor arrived and moved the emotional Albert to a private room “for a regular soft pat down,” she said, noting that all of her bags were still searched.
“The 2 TSA agents in my video went too far,” wrote Albert. “I hope no one ever experiences this.”
Albert told PIX11 of the experience, “It was overwhelming and horrific. I could not believe what was happening.”
According to the TSA website, those with TSA Precheck do not need to remove their shoes. Further, if a passenger has a medical condition, they also do not need to remove their shoes. Necessary medication and creams are allowed, but the passenger must inform the TSA officer before the screening begins and the product must pass through an X-ray scanner.
In a statement to PIX11, the TSA said, “The Transportation Security Administration takes reports of alleged impropriety very seriously.”
“TSA is currently looking into the specific details as to what occurred during the screening process to ensure our security protocols were followed,” the statement continued. “We regret any distress the security screening process may have caused the passenger. We will work with the passenger directly to address her concerns.”
