# data[].attributes.headline
Trying to stop cancer by specifically targeting the metastasis process

# data[].attributes.subject
Trying to stop cancer by specifically targeting the metastasis process

# data[].attributes.attachment_link.readable_text
Hasini Jayatilaka was a sophomore at the Johns Hopkins University working in a lab studying cancer cells when she noticed that when the cells become too densely packed, some would break off and start spreading.

She wasn't sure what to make of it, until she attended an academic conference and heard a speaker talking about bacterial cells behaving the same way. Yet when she went through the academic literature to see if anyone had written about similar behavior in cancer cells, she found nothing.

Seven years later, the theory Jayatilaka developed early in college is now a bona fide discovery that offers significant promise for cancer treatment.

Jayatilaka and a team at Johns Hopkins discovered the biochemical mechanism that tells cancer cells to break off from the primary tumor and spread throughout the body, a process called metastasis. Some 90 percent of cancer deaths are caused when cancer metastasizes. The team also found that two existing, FDA-approved drugs can slow metastasis significantly.

Amy Davis / Baltimore Sun

Hasini Jayatilaka, left, a post-doctoral fellow and Denis Wirtz, professor of chemical and biomedical engineering, who work together at the Institute of NanoBioTechnology at Johns Hopkins University, discuss their discovery that a biochemical signaling process that causes the spread of cancer cells can be slowed down with the use of two existing drugs.

Hasini Jayatilaka, left, a post-doctoral fellow and Denis Wirtz, professor of chemical and biomedical engineering, who work together at the Institute of NanoBioTechnology at Johns Hopkins University, discuss their discovery that a biochemical signaling process that causes the spread of cancer cells can be slowed down with the use of two existing drugs.

(Amy Davis / Baltimore Sun)

"A female patient with breast cancer doesn't succumb to the disease just because she has a mass on her breast; she succumbs to the disease because [when] it spreads either to the lungs, the liver, the brain, it becomes untreatable," said Jayatilaka, who earned her doctorate in chemical and biomolecular engineering this spring in addition to her earlier undergraduate degree at Hopkins.

"There are really no therapeutics out there right now that directly target the spread of cancer. So what we came up with through our studies was this drug cocktail that could potentially inhibit the spread of cancer."

The study was published online May 26 in the journal Nature Communications. The next step for the team is to test the effectiveness of the drugs in human subjects.

Typically, cancer research and treatment has focused on shrinking the primary tumor through chemotherapy or other methods. But, the team said, by attacking the deadly process of metastasis, more patients could survive.

"It's not this primary tumor that's going to kill you typically," said Denis Wirtz, Johns Hopkins' vice provost for research and director of its Physical Sciences-Oncology Center, who was a senior author on the paper.

Jayatilaka began by studying how cancer cells behave and communicate with each other, using a three-dimensional model that mimics human tissue rather than looking at them in a petri dish. Many researchers believe metastasis happens after the primary tumor reaches a certain size, but Jayatilaka found it was the tumor's density that determined when it would metastasize.

"If you look at the human population, once we become too dense in an area, we move out to the suburbs or wherever, and we decide to set up shop there," Jayatilaka said. "I think the cancer cells are doing the same thing."

When the tumor reaches a certain density, the study found, it releases two proteins called Interleukin 6 and Interleukin 8, signaling to cancer cells that things had grown too crowded and it was time to break off and head into other parts of the body.

Previously, Wirtz said, the act of a tumor growing and the act of cancer cells spreading were thought to be very separate activities, because that's how it appeared by studying cancer cells in a petri dish, rather than the 3-D model the Hopkins team used. Many researchers study only cancer cell growth or its spread, and don't communicate with each other often, he said.

Once the cancer cells start to sense the presence of too many other cancer cells around them, they start secreting the Interleukin proteins, Wirtz said. If those proteins are added to a tumor that hasn't yet metastasized, that process would begin, he said.

The team then tested two drugs known to work on the Interleukin receptors to see if they would block or slow metastasis in mice. They found that using the two drugs together would block the signals from the Interleukin proteins that told the cancer cells to break off and spread, slowing - though not completely stopping - metastasis.

The drugs the team used were Tocilizumab, a rheumatoid arthritis treatment, and Reparixin, which is being evaluated for cancer treatment.

The drugs bind to the Interleukin receptors and block their signals, slowing metastasis.

Though metastasis was not completely stopped, Jayatilaka said, the mice given the drug cocktail fared well and survived through the experiment. She said adding another, yet-to-be-determined drug or tweaking the dose might stop metastasis entirely.

Contrary to the hair loss, nausea and other negative side effects patients undergoing chemotherapy suffer, Wirtz said the side effects from the drugs used in the study would be minimal.

Anirban Maitra, co-director of a pancreatic cancer research center at the MD Anderson Cancer Center at the University of Texas, cautioned that clinical trials in humans are needed to prove the theory.

"There's a risk that something that looks so great in an animal model won't pan out in a human," he said.

But Maitra said the study looked promising, in particular because the researchers had used drugs already on the market. It can take a decade to identify a drug that would perform similarly and get it approved, and many similar observations don't advance because of the time and expense it can take to get drug approval, he said.

Muhammad Zaman, a professor and cancer expert at Boston University, called the Hopkins discovery "exciting."

"This paper gives you a very specific target to design drugs against," he said. "That's really quite spectacular from the point of view of drug design and creating therapies."

Zaman said it was important for cancer researchers to use engineering to better understand cancer, as the Hopkins team did.

"This really brings cancer and engineering together in a very unique way, and it really takes an approach that is quantitative and rigorous," he said. "We have to think of cancer as a complex system, not just a disease."

Wirtz predicted a future where cancer would be fought with a mix of chemotherapy to shrink the primary tumor and drug cocktails like the one the Hopkins team developed to ensure it would not metastasize. He compared such a treatment to how HIV/AIDS is treated today.

"We're not going to cure cancer with one therapy or even two therapies; it's going to be drug cocktails," Wirtz said. "That's what saved the day with HIV/AIDS."

Immunotherapy, which uses the body's immune system to fight cancer, also could play a role in a combined method, Wirtz added.

"We're, in research, sometimes incentivized to look at one pathway at a time, one type of cancer at a time," Wirtz said. "I think oncology has started realizing we're going to need more than one approach."

# data[].attributes.attachment_link.title
Johns Hopkins researchers say they've unlocked key to cancer metastasis and how to slow it

# data[].attributes.attachment_link.description
Jayatilaka and a team at Johns Hopkins discovered the biochemical mechanism that tells cancer tells to break off and spread throughout the body, a process called metastasis. Some 90 percent of cancer deaths are caused when cancer metastasizes. They also found that two existing, FDA-approved drugs can severely slow metastasis.

# data[].attributes.body
This video builds on the topics and vocabulary covered during the week of "Combating Cancer".

# data[].attributes.attachment_link.description
This animation created by Nature Reviews Cancer and Nature Reviews Immunology illustrates how tumour cells are sensed and destroyed by cells of the immune system and how tumours can evolve to evade immune-mediated elimination. Scientists are developing new immunotherapies that help the immune system to 'fight back' - the animation explains how these exciting new drugs work.

# data[].attributes.headline
New Gene-Altering Leukemia Treatment (July 12, 2017)

# data[].attributes.subject
New Gene-Altering Leukemia Treatment (July 12, 2017)

# data[].attributes.body
Very recent!

# data[].attributes.attachment_link.readable_text
One of those patients, Emily Whitehead, now 12 and the first child ever given the altered cells, was at the meeting of the panel with her parents to advocate for approval of the drug that saved her life. In 2012, as a 6-year-old, she was treated in a study at the Children's Hospital of Philadelphia. Severe side effects - raging fever, crashing blood pressure, lung congestion - nearly killed her. But she emerged cancer free, and has remained so.

"We believe that when this treatment is approved it will save thousands of children's lives around the world," Emily's father, Tom Whitehead, told the panel. "I hope that someday all of you on the advisory committee can tell your families for generations that you were part of the process that ended the use of toxic treatments like chemotherapy and radiation as standard treatment, and turned blood cancers into a treatable disease that even after relapse most people survive."

The main evidence that Novartis presented to the F.D.A. came from a study of 63 patients who received the treatment from April 2015 to August 2016. Fifty-two of them, or 82.5 percent, went into remission - a high rate for such a severe disease. Eleven others died.

"It's a new world, an exciting therapy," said Dr. Gwen Nichols, the chief medical officer of the Leukemia and Lymphoma Society, which paid for some of the research that led to the treatment.

The next step, she said, will be to determine "what we can combine it with and is there a way to use it in the future to treat patients with less disease, so that the immune system is in better shape and really able to fight." She added, "This is the beginning of something big."

At the meeting, the panel of experts did not question the lifesaving potential of the treatment in hopeless cases. But they raised concerns about potentially life-threatening side effects - short-term worries about acute reactions like those Emily experienced, and longer-term worries about whether the infused cells could, years later, cause secondary cancers or other problems.

Oncologists have learned how to treat the acute reactions, and so far, no long-term problems have been detected, but not enough time has passed to rule them out.

Patients who receive the treatment will be entered in a registry and tracked for 15 years.

Treatments involving live cells, known as "biologics" are generally far more difficult to manufacture than standard drugs, and the panelists also expressed concerns about whether Novartis would be able to produce consistent treatments and maintain quality control as it scaled up its operation.

Another parent at the meeting, Don McMahon, described his son Connor's grueling 12 years with severe and relapsing leukemia, which started when he was 3. Mr. McMahon displayed painful photographs of Connor, bald and intubated during treatment. And he added that chemotherapy had left his son infertile.

A year ago, the family was preparing for a bone marrow transplant when they learned about the cell treatment, which Connor then underwent at Duke University. He has since returned to playing hockey. Compared with standard treatment, which required dozens of spinal taps and painful bone marrow tests, the T-cell treatment was far easier to tolerate, Mr. McMahon said, and he urged the panel to vote for approval.

A third parent, Amy Kappen, also recommended approval, even though her daughter, Sophia, 5, had died despite receiving the cell treatment. But it did relieve her symptoms and give her a few extra months. Sophia's disease was far advanced, and Ms. Kappen thought that if the treatment could have been given sooner, Sophia might have survived.

"We hope that more families have a longer time with their children fighting this evil disease, and our children deserve this chance," she said.

The treatment was developed by researchers at the University of Pennsylvania and licensed to Novartis.

Use will not be widespread at first because the disease is not common. It affects only 5,000 people a year, about 60 percent of them children and young adults. Most children are cured with standard treatments, but in 15 percent of cases - like Emily's and Connor's - the disease does not respond, or it relapses.

Analysts predict that these individualized treatments could cost more than $300,000, but a spokeswoman for Novartis, Julie Masow, declined to specify a price.

Although the figure may seem high, people with cancer often endure years of expensive treatment and repeat hospital stays that can ultimately cost even more.

Because the treatment is complex and patients need expert care to manage the side effects, Novartis will initially limit its use to 30 or 35 medical centers where employees will be trained and approved to administer it, the company said.

As to whether the treatment, known as CTL019 or tisagenlecleucel (pronounced tis-a-gen-LEK-loo-sell), will be available in other countries, Ms. Masow said by email: "Should CTL019 receive approval in the U.S., it will be the decision of the centers whether to receive international patients. We are working on bringing CTL019 to other countries around the world." She added that the company would file for approvals in the European Union later this year.

By late November 2016, 11 of the 52 patients in the study who went into remission relapsed. Twenty-nine were still in remission. Eleven others had further treatments, like bone marrow transplants. One patient was not available for assessment. Three who had relapses died, and one who did not relapse died from a new treatment given during remission. The median duration of remission is not known because it has not been reached: Some patients were still well when last checked.

Researchers are still debating about which patients can safely forgo further treatment, and which might need a bone marrow treatment to give the best chance of a cure.

The treatment requires removing millions of a patient's T-cells - a type of white blood cell often called soldiers of the immune system - and genetically engineering them to kill cancer cells. The technique employs a disabled form of H.I.V., the virus that causes AIDS, to carry new genetic material into the T-cells to reprogram them. The process turbocharges the T-cells to attack B-cells, a normal part of the immune system that turn malignant in leukemia. The T-cells home in on a protein called CD-19 that is found on the surface of most B-cells.

The altered T-cells are then dripped back into the patient's veins, where they multiply and start fighting the cancer.

Dr. Carl H. June, a leader of the University of Pennsylvania team that developed the treatment, calls the turbocharged cells "serial killers." A single one can destroy up to 100,000 cancer cells.

Because the treatment destroys not only leukemic B-cells but also healthy ones, which help fight germs, patients need treatment to protect them from infection. So every few months they receive infusions of immune globulins.

In studies, the process of re-engineering T-cells for treatment sometimes took four months, and some patients were so sick that they died before their cells came back. At the meeting, Novartis said the turnaround time was now down to 22 days. The company also described bar-coding and other procedures used to keep from mixing up samples once the treatment is conducted on a bigger scale.

Michael Werner, a lawyer and expert on gene and cell technologies and regulation, and a partner at Holland and Knight in Washington, said that results so far proved that T-cell treatment works.

"The fact that it can be done means more people will go into the field and more companies will start developing these products." He added, "I think we're in for really exciting times."

# data[].attributes.attachment_link.title
F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment

# data[].attributes.attachment_link.description
One of those patients, Emily Whitehead, now 12 and the first child ever given the altered cells, was at the meeting of the panel with her parents to advocate for approval of the drug that saved her life. In 2012, as a 6-year-old, she was treated in a study at the Children's Hospital of Philadelphia.

# data[].attributes.headline
Tackling Brain Cancer with Immunotherapy

# data[].attributes.subject
Tackling Brain Cancer with Immunotherapy

# data[].attributes.body
good follow-up to NPR radio segment on Senator John McCain's brain cancer diagnosis

# data[].attributes.attachment_link.readable_text
Using the immune system to beat cancer is quickly becoming a promising new strategy for battling tumors. But most of the success so far has been with blood cancers like lymphomas and leukemias. Immunotherapy, as it's called, has yet to prove itself with solid tumors like breast, prostate, lung, colon and brain cancers.

But in a report published in the New England Journal of Medicine, researchers led by Dr. Behnam Badie from the City of Hope Beckman Research Institute and Medical Center say that the same immune-based therapy that is successful against blood cancers also helped a patient with advanced brain cancer.

The 50-year-old man with glioblastoma, a particularly aggressive type of brain tumor, had already been treated with surgery, radiation and anti-tumor drug therapies. Despite these treatments, his cancer had returned and also spread to other parts of his brain and spinal cord. Badie and his team extracted immune cells from him, then engineered them to express proteins on their surface that would recognize and destroy glioblastoma tumor cells. After surgery to remove the bulk of the brain tumor, Badie and his colleagues directly injected the site with the modified immune cells (called chimeric antigen receptor T cells, or CAR T cells) six times, and the remaining part of this tumor stopped growing.

Other smaller growths in the brain continued to grow, however, so the patient received 10 more doses of the CAR T cells injected into the cavities in the brain, called the ventricles. This is the first time that immune cells have been injected into these brain regions, because introducing anything into the ventricles can cause dangerous and possibly deadly inflammation. The man did not develop such serious complications, however, and after about four months, these tumors too started to shrink. By six months, almost all had disappeared.

If the patient had not received the CAR T therapy, he likely would only have survived a few weeks after his cancer recurred, says Badie. But after being treated with the immune therapy, his cancer did not grow or recur for nearly eight months. "If we can do the same for other patients, that would be an amazing accomplishment that many decades of work and research on glioblastoma have never done," says Badie, whose own father passed away a decade ago from glioblastoma.

The patient is one of nine in the trial, and so far, many of the other people are having similar experiences on the therapy. Based on this man's case, his team is hoping to now inject not just the tumor site but also the ventricular space in the brain, since that may help control spread of the cancer.

It's also becoming clear that more than one type of modified immune cells may have to be enlisted. The tumors in the first patient remained under control for almost eight months, but the cancer returned after that in new parts of the brain. Badie says it's not obvious why, but his analysis showed that these tumors did not contain much of the protein targeted by the CAR T cells that were injected. It's possible that the immune cells had destroyed most of the cancer cells expressing the original protein, so other cancer cells with other proteins began to proliferate and survive.

Badie is hoping to take advantage of this information and introduce immune cells with different tumor-targeting proteins. Eventually, these proteins would also be tailored to be specific to each patient's cancer - a precision medicine approach to controlling cancer. These results are the first encouraging sign that the immunotherapy that is helping more people with blood cancer might also be effective for people with solid tumors like brain cancers.

# data[].attributes.attachment_link.title
Experimental Brain Cancer Treatment Is a Success

# data[].attributes.attachment_link.description
Using the immune system to beat cancer is quickly becoming a promising new strategy for battling tumors. But most of the success so far has been with blood cancers like lymphomas and leukemias. Immunotherapy, as it's called, has yet to prove itself with solid tumors like breast, prostate, lung, colon and brain cancers.

# data[].attributes.headline
Hope and Hype: Immunotherapy the new hope for cancer treatment

# data[].attributes.subject
Hope and Hype: Immunotherapy the new hope for cancer treatment

# data[].attributes.attachment_link.readable_text
Some hospitals and health care systems call it a " miracle in the making" and a " game- changer." It's a treatment approach that harnesses the body's own immune system to target and attack a disease, such as cancer. Immunotherapy can come in many forms -- vaccines, antibody or cellular therapies, or drugs -- and can be received through an injection, a pill or capsule, a topical ointment or cream, or a catheter.

Yet as promising as the therapy seems, could the spotlight on immunotherapies detract from other areas of cancer research? Some experts argue yes, while many others don't seem concerned.

While other treatment options -- from targeted therapy to chemotherapy -- still and will continue to play an important role in cancer research, immunotherapy simply expands the options and possibilities for patients, said Dr. Jeff Weber, medical oncologist and deputy director of NYU's Perlmutter Cancer Center in New York, who added that he has seen many of his own patients respond positively to immunotherapy.

"It's made a big impact in the field in a sense that influential investigators in many different fields are now quite interested in immunotherapy," said Weber, who will be among the researchers attending the ASCO meeting.

"Many companies are interested in immunotherapy, and there's a significant weight of creative and capable minds now devoted to that field," he said. "Obviously the major progress we've seen is the benefit to patients, but the other advance is now the increasing attention being drawn to the field and the large number of really smart, capable, creative, and clever people that are now in the business, and you've got to believe that that's going to lead to even more advances."

However, the history of cancer research is one of episodic fads, said Dr. Vinay Prasad, a hematologist-oncologist and assistant professor of medicine at the Oregon Health and Sciences University. To him, immunotherapy might just be another fad.

"The problem is, when fads are in vogue, we neglect everything outside the fad. We spend disproportionate energy chasing what's new and forget the most rational science portfolio is broad; the most optimal portfolio is broad," he said. "There are truly some dramatic responses with immunotherapy, but like many cancer fads, it is easy to believe that the early success will extend to all cancers, and over and over, we have learned that there is no one solution to cancer."

On the other hand, a swelling interest in immunotherapy could enhance -- rather than inhibit -- other research fields, leading to some unexpected solutions, said Dr. Philip Greenberg, head of immunology at the Fred Hutchinson Cancer Research Center in Seattle and a professor at the University of Washington.

"Immunotherapy is going to be a critical and essential component of cancer care. It's becoming increasingly evident that even for people who were achieving complete responses to standard chemotherapy in the past, there was probably a component of their immune system that was critical in making that work," Greenberg said.

"Using therapies that target different aspects of a cancer, to try to bring them together so that they synergize, that will unquestionably be a real focus in the next half-decade," he said. "So, we're going to see new forms of combination therapies."

'Oncologists are putting their eggs in two baskets'

The research field already has seen dramatic responses in melanoma, kidney, lymphoma, lung cancer and other cancers using immunotherapies, said Dr. Otis Brawley, chief medical officer at the American Cancer Society, who will be attending this year's oncology society meeting.

"I personally have seen patients with widely metastatic disease have remission and have long asymptomatic periods with good quality of life. Immunotherapy deserves support so that it can be further developed," he said.

At the same time, Brawley added, there are other modalities that deserve equal support.

"While I would not give up on the old and newer cytotoxic chemotherapies, the hormones and the hormone blockers, I also do not see this as either/or," he said. "Both areas are fertile ground for more research. I would like to see all of these modalities and several others pursued and investigated."

As for immunotherapy, research showing that the drugs ipilimumab and nivolumab stopped melanoma from advancing for nearly a year in 58% of cancer cases garnered excitement at the ASCO meeting in 2015. Many other studies showing the promise of immunotherapy also have been presented at the meetings since then.

"I suspect that ASCO will be just like the last few," Prasad said of this year's meeting, which he will miss due to a time conflict. "Immunotherapy will be showered with praise; there will be little mention of the downsides, harms or costs or, worst of all, that it may have limits in fighting cancer."

Food and Drug Administration regulations, potential side effects and costs mean that only a small percentage of cancer patients may benefit from immunotherapy today, Prasad said. Immunotherapy side effects include possible skin reactions, flu-like symptoms, heart palpitations, diarrhea, infection, arthritis, or severe or even deadly allergic reactions. In 2015, it was estimated that ipilimumab and nivolumab ranged in cost from about $100,000 to $150,000, respectively, for a course of therapy.

Prasad and Nathan Gay, an oncology fellow at Oregon Health and Science University, co-authored an editorial in STAT News in which they used US national cancer patient data and FDA approvals of immunotherapy treatments to calculate the possible percentage of patients who currently could benefit from immunotherapy.

The editorial, published in March, showed that only about 8% of all cancer patients would benefit, if they could get access to and afford immunotherapy drugs, since the treatment has been approved for only a few cancers.

"Since that article, we have had some new data," Prasad said of the editorial. "Maybe the number is as high as 12% or 15% at present, and it may peak at 15% or 25%. That would be a great success, but to me, the glass will still be 75% empty."

Weber, however, prefers to view the glass as half-full.

Those numbers don't take into account the trajectory of how immunotherapy drugs are being developed, Weber said.

In other words, the numbers in the editorial paint an unfair portrait of the beneficial impact immunotherapy could have for cancer patients since the immunotherapy field is still growing, he said.

"When you contemplate the fact that there are hundreds -- literally, I think the last count it was something like 800 combination immunotherapy trials going on in different indications -- you've got to figure that the number or proportion of patients that will benefit from these drugs is going to expand over the next decade," Weber said.

"Potentially, in the future, my belief is that virtually any cancer patient would be a candidate (for immunotherapy)," he said. "The best is yet to come."

Greenberg also called the editorial pessimistic and disappointing.

As for the challenges that may come with bringing immunotherapy and other cancer therapies together, potential solutions are in the works in the form of personalized medicine, Greenberg said.

Personalized medicine involves tailoring and even combining individual treatments for patients based on their genetics and their disease.

"Personalizing therapies is a critical way of making therapies both more effective, less toxic and, in a sense, potentially less expensive in the long run, because you eliminate things that are not likely to be effective in a particular patient," Greenberg said. "Personalizing medicine to a patient's disease is going to be a critical component."

Prasad isn't convinced personalized medicine holds all the answers.

"I joke that oncologists are putting their eggs in two baskets. Immunotherapy is one. The other is the use of personalized treatment, the idea we will sequence entire genomes and find the drug that will halt the cancer," he said. "These are two most active areas. What has fallen out of favor is research into drugs that target cellular division or drugs that target resistance mechanisms," such as some chemotherapies.

Nonetheless, for advances in all areas of cancer treatment research, Prasad and Greenberg called for more funding. Overall, "what is really desperately needed is increased funding for cancer research," Greenberg said.

As Brawley said, "We have lots of promising avenues of investigation without enough money to do the research."

He pointed to othertherapies designed to target specific molecules in the growth and spread of cancer cells as showing promise, such as the chemotherapy drug crizotinib for lung cancer, and tyrosine kinase inhibitors, another class of chemotherapy drugs.

'The immune system may be able to prevent cancer'

More research is needed because combining cancer immunotherapy not only with standard treatment approaches, such as surgery, radiation and chemotherapy, but with newly emerging therapies could lead to novel insights, said Dr. Robert Vonderheide, a renowned cancer researcher and professor at the Abramson Cancer Center of the University of Pennsylvania.

He added that such insights could benefit patients.

"As breathtaking as recent successes of cancer immune therapy have been, there is more we can achieve for our patients by embracing an even broader view of cancer biology and therapy. There are great synergies, for example, from combining knowledge of immunology, genetics and tumor biology that we have only just begun to realize," said Vonderheide, who is not attending this year's oncology society meeting.

"In the future, we want to understand the whole problem: genetics, metabolism, immunology, vascular biology -- everything at once. Technology is making this multidisciplinary strategy possible," he said. "We must deeply understand the entire ecosystem driving each patient's tumor, reveal the tumor's vulnerabilities and treat the patient precisely and comprehensively."

Using the immune system to better understand cancer growth also could lead to more cancer preventive vaccines, Vonderheide said.

"Ultimately, the immune system may be able to prevent cancer in the first place," he said. "This idea is actually coming into focus with new vaccines and other approaches in clinical trials."

Vonderheide is leading vaccine-based trials for individuals at risk of hereditary breast, ovarian and other cancers associated with BRCA 1 and 2 gene mutations. The trials are conducted through the University of Pennsylvania's Basser Center for BRCA.

So far, the only cancer preventive vaccines approved in the US are human papillomavirus vaccines and hepatitis B vaccines.

Chronic hepatitis B infection can lead to liver cancer, and high-risk types of HPV have been linked to cervical, throat, anal and vaginal, vulvar and penile cancers.

As a better understanding of the body's immune system may lead to advances in vaccines and therapies, Vonderheide said, "I think we are at the end of the beginning for cancer immunotherapy."

# data[].attributes.attachment_link.keywords[]
cancer researchers weigh in on immunotherapy hype and hope - cnn.com

# data[].attributes.attachment_link.title
Hope and hype around cancer immunotherapy

# data[].attributes.attachment_link.description
Some hospitals and health care systems call it a " miracle in the making" and a " game- changer." It's a treatment approach that harnesses the body's own immune system to target and attack a disease, such as cancer.

# data[].attributes.body
Well-rounded article about immunotherapy.

# data[].attributes.attachment_link.readable_text
Artificially boosting the body's immune response against cancer is the most exciting advance in the treatment of tumors in the past couple of years. But as the jam-packed sessions at a recent scientific conference in New York City made clear, a lot of questions remain to be answered before anyone can declare victory in the war on cancer. Among them: What is the best way to kick the immune system into action? Will immunotherapy work for all sorts of people with all kinds of cancer or just for a lucky few? Is there a way to make the treatments less dangerous or expensive?

It was standing room only for many of the presentations at the first International Cancer Immunotherapy Conference, which took place from September 16 to 19.* Speaker after speaker started their talks by disclosing financial ties to a variety of companies ranging from pharmaceutical giants to their own start-ups. The audience consisted primarily of scientists and physicians. But sprinkled among the 1,400 attendees, in addition to the usual smattering of journalists, were a number of industry scouts and finance people seeking to glean the next big investment opportunity or joint project possibility.

Jill O'Donnell-Tormey, chief executive officer of the Cancer Research Institute, proclaimed 2015 "a truly special year for cancer immunotherapy." The U.S. Food and Drug Administration approved two new immunotherapy drugs, she noted, "more than half of the current cancer clinical trials include some form of immunotherapy," several groups are working on possible combination therapies and oncologists around the world are recognizing "a paradigm shift in cancer." But as exciting as these advances are, she continued, "we know that we are only at the beginning" in terms of being able to understand or broadly use them.

Reality check
The first thing you need to know about the researchers studying immunotherapy for cancer is that every one of them seemingly has a few patients who have responded extraordinarily well. Steven Rosenberg of the National Cancer Institute no doubt takes the prize in this category. In 1984, he treated a woman named Linda Taylor who had metastatic melanoma (an aggressive type of skin cancer with a survival rate of less than 10 percent after ten years). Taylor was the 81st patient to undergo the debilitating therapy and the first to respond successfully. Within a few months her tumors melted away and she remains alive and healthy today. Rosenberg-the keynote speaker at the conference-reports that his latest regimen is not as hard on patients and results in 20 percent of them experiencing "a complete and durable remission." That's about par for a lot of the immune therapies now being studied.

The second thing you need to know is that there is a reason why the body works so hard to suppress its immune reactions most of the time. The immune system has such powerful weapons in its arsenal that it can kill you faster than whatever ails you. And some of the things that doctors do to prepare the body for immune treatment are just as toxic as chemotherapy and radiation. (Indeed, for complex reasons, some immunotherapies require a dose of chemotherapy or radiation as a first step.) As Rosenberg says, "We have had some treatment-related deaths. That's been true in the field as well as in our own experience."

With those sobering caveats in mind, however, there is no mistaking the growing optimism among many cancer researchers. They are starting to figure out when it's more important to take the brakes off the body's immune responses, when to step on the accelerator to get a sluggish reaction into high gear-and when they can safely do both. As investigators study different combinations of treatments and dosages, they can see improvements in response rates and believe they are getting a better handle on some of the most severe side effects.

Hot and cold tumors
Investigators have developed several different methods for tweaking a patient's immune system so that it recognizes and attacks dangerous tumors more effectively than it otherwise would. Some of these therapies feature so-called monoclonal antibodies that interfere with cancer cells' ability to fool the immune system into ignoring them. Known as checkpoint blockade, these treatments so far appear to work best in melanoma and smoking-induced lung cancer.

There are good biological reasons for that observation. Melanoma and smoker's lung cancer both occur as a result of environmental exposure-the former from the sun's ultraviolet rays, the latter from carcinogens in tobacco smoke. As a result, lots of mutations occur in the DNA of affected cells. These mutations in turn lead to the production of many aberrant proteins, which are usually recognized by the immune system as potentially dangerous, and any cells that contain them are quickly marked for destruction.

Researchers refer to these malignancies as "hot" tumors because they sport a lot of deviant proteins that the immune system is likely to notice. They need a long time to figure out how to shield themselves from the immune system-which is part of the reason it typically takes decades for melanomas and lung cancers to grow big enough to threaten someone's life.

In these cases the immune system has already dispatched lots of immune cells to the tumor; it's just that the cancer manages to turn the defenders off whenever they arrive. Checkpoint blockade reawakens the immune cells that have already found their way inside the tumor to start killing the malignant cells in the immediate vicinity and anywhere else they may be found in the body.

Intriguingly, combining checkpoint blockade drugs results in fewer extreme side effects for patients with melanoma than for those with lung cancer. "This is something that is very recently being recognized-maybe in the past two years," says Jedd Wolchok, an oncologist at Memorial Sloan Kettering Cancer Center in New York City. "The same doses of the same medicine may not be tolerated equally in patients who have different cancers. We may have to use less medicine in patients with lung cancer. [Immunotherapy] is not one size fits all."

In any event, many kinds of cancer (such as prostate, ovarian and pancreatic) are caused by just a handful of genetic mutations. They do not create the wide range of malfunctioning proteins that would usually attract the immune system's attention. As a result, these tumors are not typically filled with lots of slumbering immune cells waiting to be reawakened; checkpoint blockade, therefore, usually doesn't work on them. They are, in the parlance of cancer immunologists, "cold" tumors.

And yet, several investigators reported on efforts to turn such cold tumors hot so they could then be targeted with immunotherapy. Padmanee Sharma, an immunologist at The University of Texas M. D. Anderson Cancer Center, for example, described a study in which men with apparently aggressive prostate cancer were given hormone treatment prior to surgery in order to first kill a few of their cancer cells before their tumor is removed. Once these cells die, the various proteins and other compounds that are usually found inside them spill into the body. Somehow, this makes it easier for the immune system to pay attention and it starts sending immune cells to tackle whatever microscopic bits of tumor might be left elsewhere in the body after the operation. Unfortunately, as Sharma told the audience, their subsequent response to immune-boosting drugs was short-lived. She and her colleagues are pursuing several different ideas, however, to make it last longer.

Finding the right balance
Indeed, the idea that you don't have to kill all the cancer cells in a tumor to get the immune system going sparked a lot of interest at the conference. Ira Mellman, Genentech's vice president of cancer immunology, wondered aloud whether "chemotherapy may in fact be, to some extent, immunotherapy." By killing a few cells, it may prime the immune system to respond better to later treatments. In some cases the release of cancer proteins jump-starts the immune response. In others a chemotherapy drug such as gemcitabine actually releases the brakes by temporarily eliminating the cells whose normal job is to tamp down the immune system.

Stanford University oncologist Ron Levy has taken this concept one step further by using low-dose radiation treatment to kill a few malignant cells in 15 patients with non-Hodgkin's lymphoma who had several visible tumors. Then he injected an experimental immunostimulatory compound directly into a single lesion in each of these patients. By doing so, he found he could lower the amount of drug he needed to trigger a reaction. Acting on a single tumor-which doesn't require as much medicine as trying to reach all the tumors in the body-was sufficient to trigger a general immune response.

Most of the patients in Levy's study exhibited some kind of response; even tumors that had not been treated started to shrink in a few people. Generally speaking, it took six months to two years to see the changes. One 38-year-old man experienced a complete response, meaning all observable signs of the cancer disappeared throughout the body-an outcome that lasted more than a year. (A "complete response" is not necessarily the same thing as a cure because undetectable amounts of cancer might still be lurking somewhere in the body.) "We're trying to make this response more common and more durable," Levy said. His next step is to try to combine this method for stimulating the immune system with monoclonal antibodies that prevent tumors from shutting the immune system down (given at 1/20th of the usual dose). "We hope to eliminate toxicity by going local and lowering the effective dose," he told meeting participants. Although Levy has started treating at least one person with this newer combo approach, he was not yet ready to share results.

Investigators presented several other promising immunotherapies at the conference but no roundup would be complete without mentioning the so-called CAR T cells, many of which have received orphan drug or "breakthrough status" by the FDA in the past 18 months.

CAR T cells are immune cells that have been genetically engineered to target tumors in a much more powerful way than normal immune cells can. To date, clinical trials conducted at Memorial Sloan Kettering, the Fred Hutchinson Cancer Research Center and the University of Pennsylvania Perelman School of Medicine have demonstrated remission rates of about 90 percent in several advanced cancers of the blood and lymph systems (again, not necessarily the same as a cure but still astounding).

"There are 300 kinds of cancer at least and they're each going to have different issues," says Carl June of the University of Pennsylvania. But, he adds, "I think we have enough tools that we can plot a course." Stay tuned.
*Four professional associations combined forces to conduct the meeting: the Cancer Research Institute, the Association for Cancer Immunotherapy (CIMT), the European Academy of Tumor Immunology and the American Association for Cancer Research.

# data[].attributes.attachment_link.keywords[]
cancer malignancy tumor immunotherapy antibodies t-cells

# data[].attributes.attachment_link.title
Cancer Immunotherapy: The Cutting Edge Gets Sharper

# data[].attributes.attachment_link.description
Artificially boosting the body's immune response against cancer is the most exciting advance in the treatment of tumors in the past couple of years. But as the jam-packed sessions at a recent scientific conference in New York City made clear, a lot of questions remain to be answered before anyone can declare victory in the war on cancer.

# data[].attributes.attachment_link.description
The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure.

# data[].attributes.headline
Tumor characteristics might influence how well immunotherapy might work.

# data[].attributes.subject
Tumor characteristics might influence how well immunotherapy might work.

# data[].attributes.attachment_link.readable_text
The molecular make-up of lung tumours could help identify patients who might benefit from immunotherapy treatment up front, a new study has found.

The phase 3 clinical trial, run by The Ohio State University Comprehensive Cancer Center in the US, suggests that immunotherapy given before other drugs could improve the outlook for certain patients with advanced lung cancer.

"This study emphasises the need to characterise patients' tumours to guide the design of clinical trials for cancer immunotherapies" - Professor Charles Swanton, Cancer Research UK

The findings are "an important step forward" in understanding which patients are likely to benefit from immunotherapy, said lead scientist Dr David Carbone.

The immunotherapy drug used in the trial - called nivolumab ( Opdivo) - is already available on the NHS for some patients with advanced lung cancer who have previously been treated with chemotherapy.

The latest trial compared nivolumab with standard chemotherapy in 530 patients who hadn't been treated with cancer drugs previously.

Nivolumab works by blocking an immune molecule called PD-1, which normally prevents the immune system from going into overdrive, but in some cancers is overproduced. Targeting this molecule releases the immune system's 'brakes' so that it can attack the tumour.

The patients all had advanced lung cancer or lung cancer that had returned, and their tumour cells carried PD-1's molecular partner PD-L1 on their surface, indicating that PD-1 blockers could be effective for them.

Overall, survival and the length of time until the disease worsened were similar between patients receiving either immunotherapy or chemotherapy. But when the researchers took into account certain characteristics of the tumours, immunotherapy showed benefits over chemotherapy.

In patients whose tumours had high levels of the PD-L1 molecule and lots of immune-stimulating genetic faults, 3 in 4 patients' tumours (75%) responded to nivolumab, compared with just 16% in those who had low levels of both. Only around 1 in 4 patients in these groups responded to chemotherapy. In addition, patients treated with nivolumab experienced fewer side effects than those given chemotherapy.

The results have been published in The New England Journal of Medicine.

Professor Charles Swanton, a Cancer Research UK expert on lung cancer, said: "Finding ways to predict whether immunotherapy will benefit patients is critical to improve survival. This study emphasises the need to characterise patients' tumours to guide the design of clinical trials for cancer immunotherapies."

To make sure that these important drugs reach patients who are most likely to benefit from them, Swanton says, future studies need to look into the role of the number of genetic faults within a tumour and select patients whose PD-L1 levels are above a certain level.

"This will have the added benefit of limiting costs and side effects of treating patients who won't benefit from this class of immune therapy," he added.

# data[].attributes.attachment_link.title
Tumour characteristics could predict immunotherapy success in lung cancer

# data[].attributes.attachment_link.description
The molecular make-up of lung tumours could help identify patients who might benefit from immunotherapy treatment up front, a new study has found. The phase 3 clinical trial, run by The Ohio State University Comprehensive Cancer Center in the US, suggests that immunotherapy given before other drugs could improve the outlook for certain patients with advanced lung cancer.

# data[].attributes.headline
Immunotherapy may have the side effect of altering hair color

# data[].attributes.subject
Immunotherapy may have the side effect of altering hair color

# data[].attributes.attachment_link.title
Lung Cancer Immunotherapy Darkens Patients' Hair | GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business | GEN

# data[].attributes.attachment_link.description
The unexpected ability of a checkpoint inhibitor to bring color back to the unpigmented hair of certain cancer patients may reveal important clues about autoimmune disorders.

# data[].attributes.body
If you heard us mention radiotherapy in class and are curious to learn more, this is a really interesting & thorough discussion of it from a medical journal-- like any other journal article, be patient with yourself and go slowly.

# data[].attributes.headline
Immunotherapy article from the journal Science (challenge)

# data[].attributes.subject
Immunotherapy article from the journal Science (challenge)

# data[].attributes.body
This is a very complicated article written by researchers, for researchers, and published in a very well-known journal-- that you can totally read. Go through the abstract and introduction slowly and look up confusing words. If you're patient with yourself, you'll be able to understand more of this stuff than you might think.

# data[].attributes.body
Oct. 6, 2014

# data[].attributes.attachment_link.readable_text
Our bodies are under constant patrol by a vigilant team of defenders. These immune system superheroes set up barriers, decide whether an invader is dangerous, and, when necessary, go to battle.

White blood cells called T cells have the crucial task of protecting us from unwelcome pathogens and unhealthy cells. But like all superheroes, T cells have their weaknesses. Cancer cells have proven to be a pernicious foe by using a kind of invisibility shield to slip by T cells' careful watch. Time after time, cancer wins.

Cancer researchers are starting to figure out how to boost the power of T cells. And it turns out that, once enhanced, they can be incredibly effective cancer killers.

How effective? The first inkling came in 2011, when a team led by Carl H. June at the University of Pennsylvania's Abramson Cancer Center showed that enhanced T cells had obliterated tumors in three patients with advanced chronic lymphoid leukemia. These patients had been running out of options, and the treatment caused their cancer to essentially disappear.

Each patient had received a treatment, known as an immunotherapy, made from a superpowered version of his own T cells. The Penn researchers used inactivated HIV to insert into T cells' DNA the instructions for a homing device that helps them find and fight cancer. After coaxing the reprogrammed cells-called CARTs, for chimeric antigen receptor T cells-into propagating, the researchers gave them back to the patient.

The results in that first CART trial were so dramatic that the researchers were incredulous. Bruce L. Levine, the director of Penn's clinical cell and vaccine production facility, who has worked with June since 1992, recalls that when the first patients to be treated with CARTs came back for their checkup, "We'd get some lab data back, and it would be like, 'The tumor cell counts were gone,' or 'The scans were clean,' and Carl would say, 'We've got to run that again.' "

The magnitude of the effect was a complete surprise. Depending on the patient, up to 8 lb of tumor melted away in a mere three weeks. And the engineered T cells kept up their battle. Six months after the infusion, patients came back to check whether the disease had resurfaced: In a test of a million cells, the scientists couldn't detect a single tumor cell, Levine recalls.

The publication of the results kicked off a frenzy as drug firms and investors tried to get a foothold in a technology once considered a purely academic pursuit-cool science but way too challenging to commercialize. Since then, the major medical centers working on CART technology have spawned multiple start-ups, and venture capitalists have been more than happy to back their efforts.

Big pharma has also climbed on board. Novartis has a close relationship with Penn and an internal team of 320 researchers working on cell and gene therapies. This year Pfizer and GlaxoSmithKline also made significant commitments to modifying T cells through partnerships with biotech firms. Overall, since 2011, more than $800 million in public and private investment has flowed into a handful of companies developing the technology.

But commercializing CARTs in multiple cancer types is not going to be easy. Despite spending nearly a quarter-century on CARTs, scientists still need to make improvements throughout the process-from the point when T cells are isolated from a patient's blood right up to when they are given back to the patient.

Key questions include: What is the best design for a CART? How many reengineered T cells are enough to be potent? What is the best way to manufacture CARTs to ensure they are safe, effective, and affordable? Perhaps the biggest question is whether this technology will be relevant in solid tumors, where the hurdles to designing a CART are much higher.

Industry veterans are encouraged that the mad rush into the field was accompanied by a large amount of cash. The hefty investment in CART technology "is an appreciation-maybe for the first time in biotech-that this is not a trivial process and we need a huge war chest," says Mitchell H. Finer, chief scientific officer of Bluebird Bio, which is developing CART therapies in partnership with Celgene. Turning the technology into a product is going to be complicated, Finer adds.

Given that the immune system's job is to find and destroy interlopers, it makes sense that scientists would want to direct it to find and destroy cancer cells. But researchers in industry and academia have spent decades searching for a good way to harness the immune system effectively.

The challenge is that cancer has sneaky ways of hiding from T cells. While scouting for invaders, a T cell stops regularly to assess whether a substance is out of the ordinary. If it is, the cell kills it. Checkpoint proteins mediate that process, alerting T cells to stop their attack before damage is done to healthy tissue. Cancer cells take refuge from immune attacks by hijacking the checkpoint protein's signaling system.

The tide for cancer immunotherapy turned in 2011, when Bristol-Myers Squibb gained approval for the melanoma treatment Yervoy. The antibody inhibits the checkpoint protein CTLA-4, allowing T cells to get back in the battle. Although not a cure, Yervoy validated the idea of harnessing the immune system. Excitement has built as data have emerged for other checkpoint inhibitors, culminating last month in the approval of Merck & Co.'s Keytruda, a melanoma treatment.

Companies are encouraged by the potential for these immunotherapies, particularly as researchers learn how to maximize their efficacy by combining them with other drugs. But they have limitations. "There are also cancer patients who are really, really sick, and their immune systems are all beaten up," says John C. Lin, Pfizer's vice president of immunotherapy. "They may not have enough T cells left for these checkpoint inhibitors to work on."

CART immunotherapy goes a step further. It overcomes the limitations of a weakened immune system by generating an army of reprogrammed T cells outside the patient's body. Moreover, those reprogrammed T cells often stick around to keep up the battle if cancer should return.

The CARTs now undergoing clinical trials-from Penn-Novartis, Juno Therapeutics, Kite Pharma, and academic labs-all use the same basic construct. A vector embeds the DNA for the chimeric antigen receptor, or CAR, into the T cell; cells are multiplied and then returned to the patient.

The CAR includes all the components needed to give the T cell its enhanced powers: an antibody domain that sits on the outside of the T cell to bind to the tumor cell; a hinge and transmembrane domain that tethers the antibody to the cell; and costimulatory and essential activity domains, which sit inside the T cell and together signal it to divide.

So far, most of the CARTs in or nearing clinical studies seek out CD19, a protein found on B cells, a type of white blood cell that goes awry in many blood cancers. The differences in companies' approaches boil down to nuances in design-the vector chosen or the choice of costimulatory domain or hinge. But these subtleties matter, Bluebird's Finer explains. CARTs are normally expressed "in a very carefully coordinated fashion," he says. "They're not beads on a string, and so significant thought needs to be put into the details of their design."

Design is only one piece of making an immunotherapy work. Researchers also must decide how many reprogrammed cells are needed to elicit a safe and strong response against cancer.

Figuring out how much CART therapy to give a patient might require some mental jujitsu for those accustomed to the traditional ways of developing small-molecule or biologic drugs. Typically, drug developers run studies of different dosages of a medicine and make a tidy graph to determine how much can be given before side effects become worrisome.

But reprogrammed T cells, if working properly, should swiftly multiply inside the patient. Moreover, the therapeutic effect is dictated by the potency of the CART itself, which is a result of its design and how it was manufactured but can also depend on the state of the cancer patient, who might be very young or quite old and who often has been treated with many other drugs.

"I suppose the honest answer is that we really don't know what the right dose is in a lot of situations," says John Maher, an immunologist who leads the CAR mechanics lab at King's College London. "These are living drugs. The cells can divide in the patient, so the dose you put in does not necessarily equate to the therapeutically active dose."

Determining appropriate dosing for cellular therapy is "a question everybody in the field is trying to pinpoint," says Margo R. Roberts, chief scientific officer of Kite Pharma. The current strategy is to infer from clinical data-in other words, to monitor safety and efficacy in individual cancer patients. But Roberts notes that the dose for the anti-CD19 CARTs has varied from as much as 30 million per kilogram of body weight to as low as 1 million per kilogram, the amount given in clinical trials of Kite's lead CART.

Biotech executives all point to the results of those first three patients in the Penn study as evidence of the vagaries of dosage. Penn scientists had trouble manufacturing enough of the reprogrammed T cells for one patient. They ended up giving him a dose that was an order of magnitude lower than the other two received.

Remarkably, the man not only responded, but his cancer went into remission. "It tells you that numbers aren't the only thing that matters," Bluebird's Finer says. "If you have the right cells and you treat them right, you can have an effective response."

Getting the dosage right is as much about safety as it is about potency. CARTs quickly multiply, an effect that can obliterate cancer cells but also cause deadly side effects.

The concern was brought to the forefront this spring, when Juno, formed less than a year ago with a star-studded list of scientific founders, temporarily stopped adding new patients to its CART studies after several deaths. The halt-since lifted-was meant to give the company time to consider dosing and the overall health of patients it enrolled.

Paradoxically, the main safety problems arise when CARTs do too good a job of killing cancer cells. When T cells encounter a foe, they unleash cytokines, proteins that aid in and regulate the immune response. After CARTs rapidly multiply inside a patient's body, oncologists have seen a cytokine "storm," a dangerous-even deadly-release of the proteins. The other concern is tumor lysis syndrome, which occurs when a massive amount of dying tumor cells release metabolites that build up in the kidney.

Some progress is being made toward predicting the right number of cells to administer. "We continue to work this out diligently on a per-patient basis because, let's face it, we're dealing with personalized therapies where each individual is the control and each individual is unique," says Usman Azam, head of Novartis's cell and gene therapies unit.

Novartis and its collaborators at Penn have established a dose-ranging system that they expect to describe at the annual meeting of the American Society of Hematology in December. And because doctors now anticipate the side effects, they can try to mitigate serious damage to patients, Azam notes.

Two companies have responded to the dosing dilemma by embedding a gene in the CART that will be activated only in the event of a health crisis. The French biotech firm Cellectis has incorporated a cell-surface marker that, when turned on by the cancer drug Rituxan, causes the number of engineered T cells to plummet. Cellectis hopes to begin human tests of its first treatment a year from now.

Bellicum Pharmaceuticals has added a cell death switch to its CARTs that is activated by an otherwise inert small molecule. The company has shown in animal studies that it can eliminate the majority of the engineered T cells in as little as half an hour, according to Chief Executive Officer Thomas J. Farrell. Bellicum aims to put its first CART with the safety switch into clinical trials by the end of next year.

CARTs are proving in clinical studies to be effective killers of blood cancer, but it's not clear yet if they can be turned into successful commercial products. Currently, most CARTs are made from scratch using a patient's own T cells, putting the technology at the frontier of personalized medicine.

"This doesn't fall into the kind of paradigm that big pharma uses as they try to develop drugs," says Steven A. Rosenberg, chief of the National Cancer Institute's surgery branch, who in 2010 published the first report of a patient responding to CART therapy. "They want vials on a shelf that are stable and can be widely distributed for treatment. And they don't really care if it costs half a billion dollars to make the first vial, as long as they can make the second vial for a dollar."

Companies are working diligently to understand how to translate what has primarily been an academic endeavor into an industrial process. Manufacturing CARTs for a wide audience will mean figuring out how to make individualized therapies quickly, consistently, and affordably.

"The thing that has kept many players away from this space is fear of manufacturing," Novartis's Azam says. But Novartis believes the challenge is surmountable. Soon after forging its pact with Penn, the company bought a manufacturing plant in Morris Plains, N.J., from Dendreon, a Seattle-based company that developed an approved, but commercially unsuccessful, personalized treatment for prostate cancer. Novartis has since been working diligently on how to ease the complexity and cost of CARTs.

Bringing down the cost of personalized immunotherapies will require improvements at every point in the process. Companies hope that properly designing CARTs will improve potency and cut down on the number of T cells needed to elicit a response. They are also honing the manufacturing process to ensure patients can be treated swiftly and safely.

Some firms are trying to work around the manufacturing challenge by developing "off the shelf" CARTs. Pfizer entered the field through a deal with Cellectis, which is developing CARTs that use donor T cells modified for use in a broad patient population. Like its competitors, Cellectis uses a viral vector to insert instructions for the CAR into T-cell DNA. But the company takes an additional measure: Using a gene-editing technology that precisely snips out segments of DNA, it strips the donor T cells of the proteins that would cause a patient to reject them as foreign.

The personalized approach "is very time-consuming, laborious, and also very expensive," Pfizer's Lin says. "We think there should be a better way." He points out that some 300 patients are on Penn's waiting list for CARTs for lack of capacity to make the personalized therapies. "Clearly it's a problem that needs to be solved, so that's why we're drawn to the technology Cellectis is working on," Lin adds.

Penn notes that last month it began construction of a 30,000-sq-ft facility-funded in part by Novartis-that, when completed, will enable more patients to be taken on.

But the manufacturing challenge isn't just about logistics and economics. Research suggests that how CARTs are made could have an impact on their potency. As they multiply in the manufacturing process, T cells also become differentiated-that is, they change into other types of T cells, which can cause them to lose their ability to propagate once they are returned to the patient.

Moreover, T cells can undergo only so many divisions before they experience burnout. "Just like us, as we get older, we get exhausted more easily," Bluebird's Finer explains. Researchers are learning how to track so-called exhaustion markers on T cells to understand what they mean for the potency of a cell-based immunotherapy.

While companies sort out the nuances of bringing CARTs for blood cancer to market, they are also considering how to apply the technology to the wider world of solid tumors. It will be tricky. In CD19, researchers have as close to an ideal target as is possible in cancer. The receptor sits on both normal and cancerous B cells, but patients can live without healthy B cells as long as they are given immunoglobulin replacement therapy.

Similarly safe targets on solid tumors are less obvious. Moreover, solid tumors are harder to access. "When you're dealing with a leukemia, you've got direct access to many of the cells circulating in the bloodstream," says King's College's Maher, who is working on a CART for solid tumors. But solid tumors often have a complex microenvironment designed to deflect an immune attack, and many scientists question whether a CART for a solid tumor can elicit anywhere near the kind of response that it can in blood cancer.

Novartis's Azam is sanguine about the prospects for moving CARTs into solid tumors, noting that the company even sees the technology being used one day in other disease areas, such as immunology. "There is clearly a very solid scientific rationale and basis for developing these in solid tumor types," he says.

Novartis and Penn scientists are actively looking at diseases, such as pancreatic cancer, where few or no treatment options exist. Referring to solid tumors, Azam says Novartis is "definitely entering into clinical studies in a small-scale setting in the very near future."

Beyond pursuit of other tumor types, researchers expect the coming years will bring new knowledge about how to pair CARTs with other treatments, particularly checkpoint inhibitors. "The cancer field really is built on combination therapy," says David D. Chang, Kite's chief medical officer. "There are a lot of discussions ongoing about combining CART therapy with other immunotherapy. I would say that the scientific rationale is strong and such a combination therapy is worth pursuing."

Despite the many kinks to be worked out on how to optimize CARTs, researchers are happy to be making real progress in empowering T cells to fight cancer. They are betting that the technology will offer results of the type only dreamed about in the oncology world.

"A lot of people have talked a lot about personalized therapies and personalized medicines, but very few have achieved something successful in this space," Azam says. "We feel we're tantalizingly close to doing that."

# data[].attributes.attachment_link.description
Our bodies are under constant patrol by a vigilant team of defenders. These immune system superheroes set up barriers, decide whether an invader is dangerous, and, when necessary, go to battle. White blood cells called T cells have the crucial task of protecting us from unwelcome pathogens and unhealthy cells.

# data[].attributes.headline
Re-Writing the Code-Gene therapy for Sickle cell anemia

# data[].attributes.subject
Re-Writing the Code-Gene therapy for Sickle cell anemia

# data[].attributes.attachment_link.readable_text
A French teenager's sickle cell disease has been reversed using a pioneering treatment to change his DNA.

The world-first procedure at Necker Children's Hospital in Paris offers hope to millions of people with the blood disorder.

Scientists altered the genetic instructions in his bone marrow so it made healthy red blood cells.

So far, the therapy has worked for 15 months and the child is no longer on any medication.

Sickle cell disease causes normally round red blood cells, which carry oxygen around the body, to become shaped like a sickle.

These deformed cells can lock together to block the flow of blood around the body. This can cause intense pain, organ damage and can be fatal.

The teenager who received the treatment had so much internal damage he needed to have his spleen removed and his hips replaced.

Every month he had to go into hospital to have a blood transfusion to dilute his defective blood.

But when he was 13, doctors at the Necker Children's Hospital in Paris did something unique.

'No sign of disease'

Doctors removed his bone marrow - the part of the body that makes blood. They then genetically altered it in a lab to compensate for the defect in his DNA that caused the disease.

Sickle cell is caused by a typo in the instructions for making the protein haemoglobin, which is densely packed into red blood cells.

A virus was used to infect the bone marrow with new, correct instructions.

The corrected bone marrow was then put back into the patient.

The results in the New England Journal of Medicine showed the teenager has been making normal blood since the procedure 15 months ago.

Philippe Leboulch, a professor of medicine at the University of Paris, told the BBC News website: "So far the patient has no sign of the disease, no pain, no hospitalisation. He no longer requires a transfusion so we are quite pleased with that.

"But of course we need to perform the same therapy in many patients to feel confident that it is robust enough to propose it as a mainstream therapy."

'Given his life back'

Prof Leboulch is nervous about using the word "cure" as this is just the first patient to come through clinical trials.

But the study does show the potential power of gene therapy to transform the lives of people with sickle cell.

"I think it's very significant, essential they've given him his life back," said Dr Deborah Gill from the gene medicine research group at the University of Oxford.

She told the BBC: "I've worked in gene therapy for a long time and we make small steps and know there's years more work.

"But here you have someone who has received gene therapy and has complete clinical remission - that's a huge step forward."

However, the expensive procedure can only be carried out in cutting-edge hospitals and laboratories, while most sickle cell patients are in Africa.

The next big challenge will be to transform this pioneering science into something that really can help millions of people.

Follow James on Twitter.

What is sickle cell disease?

Sickle cell disease is a lifelong condition caused by a faulty gene that affects how red blood cells develop

SCD mainly affects people of African, Caribbean, Middle Eastern, Eastern Mediterranean and Asian origin

People with sickle cell are often at an increased risk of contracting serious infections or they could become anaemic, which is when red blood cells cannot carry enough oxygen around the body. This can cause tiredness and shortness of breath

Some patients have regular blood transfusions - usually every three to four weeks - as a form of treatment for the condition

# data[].attributes.attachment_link.description
A French teenager's sickle cell disease has been reversed using a pioneering treatment to change his DNA. The world-first procedure at Necker Children's Hospital in Paris offers hope to millions of people with the blood disorder. Scientists altered the genetic instructions in his bone marrow so it made healthy red blood cells.

# data[].attributes.body
This website is a launchpoint for gaining a sense of worldwide trends in cancer, great interactive maps, graphs etc.

# data[].attributes.attachment_link.description
The Global Cancer Observatory (GCO) is an interactive web-based platform presenting global cancer statistics to inform cancer control and research.