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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.”
Before Debbie Bowers had surgery for breast cancer, her doctor promised that insurance would pay for reconstruction, and said she could “even go up a cup size.” But Ms. Bowers did not want a silicone implant or bigger breasts.
“Having something foreign in my body after a cancer diagnosis is the last thing I wanted,” said Ms. Bowers, 45, of Bethlehem, Pa. “I just wanted to heal.”
While plastic surgeons and oncologists aggressively promote breast reconstruction as a way for women to “feel whole again,” some doctors say they are beginning to see resistance to the surgery. Patients like Ms. Bowers are choosing to defy medical advice and social convention and remain breastless after breast cancer. They even have a name for the decision to skip reconstruction: They call it “going flat.”
“Reconstruction is not a simple process,” said Dr. Deanna J. Attai, a breast surgeon in Burbank, Calif., and a past president of the American Society of Breast Surgeons, adding that more of her patients, especially those with smaller breasts before diagnosis, were opting out of reconstruction. “Some women just feel like it’s too much: It’s too involved, there are too many steps, it’s too long a process.”
Social media has allowed these women to become more open about their decision to live without breasts, as well as the challenges, both physical and emotional, that have followed. For a recent video created by wisdo.com, a social media platform, and widely shared on Facebook, Ms. Bowers and her friend Marianne DuQuette Cuozzo, 51, removed their shirts to show their scarred, flat chests. And Paulette Leaphart, 50, a New Orleans woman whose clotting disorder prevented her from having reconstruction after a double mastectomy, walked topless from Biloxi, Miss., to Washington this summer to raise awareness about the financial struggles of cancer patients.
“Breasts aren’t what make us a woman,” Ms. Leaphart said.
The nascent movement to “go flat” after mastectomies challenges long-held assumptions about femininity and what it means to recover after breast cancer. For years, medical professionals have embraced the idea that breast restoration is an integral part of cancer treatment. Women’s health advocates fought for and won approval of the Women’s Health and Cancer Rights Act of 1998, which requires health plans to cover prosthetics and reconstructive procedures.
Since then, breast reconstruction has become standard care. More than 106,000 reconstructive procedures were done last year, a 35 percent increase since 2000, according to the American Society of Plastic Surgeons. While it is not known exactly what percentage of women opt for breast reconstruction after a mastectomy, one study found that in 2011, 63 percent of women who were candidates for the procedure chose to have it. In some parts of the United States, the number is closer to 80 percent today.
In promoting the surgery, doctors cite studies that suggest breast reconstruction improves a woman’s quality of life after cancer. But some women say that doctors focus too much on physical appearance, and not enough on the toll prolonged reconstructive procedures take on their bodies and their psyches. Up to one-third of women who undergo reconstruction experience complications. A systematic review of 28 studies found that women who went without reconstruction fared no worse, and sometimes did better, in terms of body image, quality of life and sexual outcomes.
“That’s the dirty little secret of breast reconstruction: The risk of a major complication is higher than for the average elective surgery,” said Dr. Clara Lee, an associate professor of plastic surgery at Ohio State University who performs the procedure.
Ms. Cuozzo, who appeared in the Facebook video with Ms. Bowers, spent a year having her breasts rebuilt after a double mastectomy, but after four infections in five months, she had the implants removed. The reconstruction, she said, “was getting worse than the cancer.”
While some states, including New York, now require physicians to tell women about the availability of breast reconstruction, women say they often are not informed of the option to remain flat. “I was never told there was a choice,” Ms. Cuozzo said. “I went from the breast surgeon to the plastic surgeon, and they said, ‘This is what you’re going to do.’”
Dr. David H. Song, chief of plastic surgery at the University of Chicago and immediate past president of the American Society of Plastic Surgeons, said that the risk of complications was real, but that focusing on them was like focusing on plane crashes when “millions of flights land safely.”
Given advancements in surgical techniques, “the aesthetic result can be better than the native breast,” Dr. Song said. “Patients can come out the other end looking more youthful, with a better aesthetic in her breast than before.”
But it is that kind of talk — suggesting that a reconstructed breast is an improvement on a woman’s natural breast — that enrages many women who have undergone mastectomies. For starters, a reconstructed breast is often numb and can no longer play a role in sexual arousal. It often lacks a nipple, since the nipple is usually removed in a mastectomy.
After looking at photos of reconstructed breasts, “I was slightly horrified,” said Charlie Scheel, 48, of Brooklyn, who decided against implants after a double mastectomy. “You don’t have nipples and you have scars everywhere.”
Rebecca Pine, a cancer survivor from Long Island who co-founded a photography and writing project called “The Breast and the Sea,” said, “It’s a tremendous amount to put your body through, and it’s not like we’re going to get our breasts back.”
Ms. Pine, 40, had reconstruction after her first mastectomy, but had the implant removed later when she had a prophylactic mastectomy on her other breast. “They don’t look or feel, in most cases, like our breasts,” she said. “The nerves are cut, so they’re not receptive to feel or touch.”
Dr. Susan Love, author of a best-selling book about breast health, said that doctors aiming to expand access to reconstruction may have become overly enthusiastic about the surgery.
“Surgeons became so proud of what we were able to do that we may have forgotten that not everybody may want it,” Dr. Love said.
Dr. Marisa C. Weiss, founder of breastcancer.org, said doctors should not assume every patient wants reconstructed breasts. “I’ve had go-go dancers who do not want reconstruction and nuns who say, ‘I need reconstruction,’” she said.
Some women say physicians pressured them to get implants. When Catherine Stapleton, of Florida, woke up after her mastectomy, she discovered that her breast surgeon, a woman, had left unsightly flaps of skin and tissue that could be used for breast reconstruction later, in case she changed her mind.
“When I woke up from anesthesia, I was in shock,” said Ms. Stapleton, 58, who is now facing additional major surgery to correct the first procedure.
Geri Barish, president of the Long Island advocacy group 1 in 9, said a doctor had chided her when she opted against reconstruction. “One doctor said to me: ‘How can you walk around like that? You look deformed,’” she recalled.
Support groups and social media have allowed women to share stories about the realities of reconstruction. “A lot of the women in my support group had infections, and they were surprised at how many surgeries were involved,” said Alicia Staley, 45, who stayed flat after a double mastectomy. “As I compared notes, I wondered, ‘Why are all these women doing this to themselves?’”
Coming to terms with a flat chest after breast cancer can be difficult. While some women wear a prosthesis in their bra, it is not uncommon for them to stop using it. “They’re heavy, they’re uncomfortable, and they’re in a sensitive area where you have scars,” Ms. Pine said.
Women say they take many of the clothes they wore before surgery to Goodwill and begin wearing scarves and long strands of beads to hide their flat chests. Others try to embrace their new form by having elaborate tattoos inked where they once had breasts. Ms. Pine has a lotus flower tattoo on one side and a dragonfly on the other.
Sara Bartosiewicz-Hamilton, 39, a technical writer in Kalamazoo, Mich., tried two types of implants but had a constant burning sensation and got rid of them. She then started a virtual support group called Flat and Fabulous. “We’re not anti-reconstruction,” she said. “But many women never feel it’s part of their body.”
For Kate Cloudsparks, 64, a farmer in southern Iowa who has been flat since a preventive mastectomy 21 years ago, discovering the Flat and Fabulous Facebook page this year led to her first communication ever with women who had made the same choice.
“I didn’t know anybody else like me. I was carrying it around for 20 years without having anywhere to share it,” she said. “Finally, I had an opportunity to talk about what it’s been like to live as a woman without breasts.”
