Nivolumab & Ipilimumab Immunotherapy Is A Kidney Cancer Game Changer

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Nivolumab & Ipilimumab Immunotherapy Is A Kidney Cancer Game Changer
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Posted by:
Greg Lance – Watkins
Greg_L-W

eMail: Greg_L-W@BTconnect.com

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Hi,

Immunotherapy cancer drug hailed as ‘game changer’

  • 9 October 2016
 Kidney cancer
Image copyright Science Photo Library

An immunotherapy drug has been described as a potential “game-changer” in promising results presented at the European Cancer Congress.

In a study of head and neck cancer, more patients taking nivolumab survived for longer compared with those who were treated with chemotherapy.

In another study, combining nivolumab with another drug shrank tumours in advanced kidney cancer patients.

Immunotherapy works by harnessing the immune system to destroy cancer cells.

Advanced head and neck cancer has very poor survival rates.

In a trial of more than 350 patients, published in the New England Journal of Medicine, 36% treated with the immunotherapy drug nivolumab were alive after one year compared with 17% who received chemotherapy.

Patients also experienced fewer side effects from immunotherapy.

Double hit

The benefits were more pronounced in patients whose tumours had tested positive for HPV (human papillomavirus). These patients survived an average of 9.1 months with nivolumab and 4.4 months with chemotherapy.

Normally, this group of patients are expected to live less than six months.

Early data from a study of 94 patients with advanced kidney cancer showed that the double hit of nivolumab and ipilimumab resulted in a significant reduction in the size of tumours in 40% of patients.

Of these patients, one in 10 had no sign of cancer remaining.

This compares with 5% of patients showing tumour reduction after standard therapy.

About 12,000 people are diagnosed with kidney cancer in the UK each year and an average of 12 people die from the disease each day.

Image caption Peter Waite was able to continue working as a motor technician while receiving immunotherapy treatment for cancer
Peter Waite, cancer patient

Peter’s journey

“I feel a bit of a fraud having terminal cancer because I haven’t been in pain at all,” says Peter Waite, 64, from Hertfordshire.

“There’s been nothing negative about it for me and I feel a bit embarrassed really.”

Peter started receiving combined immunotherapy (nivolumab and ipilimumab) in a clinical trial in early 2015 after doctors discovered he had a type of renal cancer several years after recovering from kidney and lung cancer.

He was told he probably had three to five years left.

Instead of being treated with chemotherapy, he spent four months receiving both immunotherapy drugs and experienced virtually no side effects, allowing him to continue working as a motor technician throughout his treatment.

Scans of his kidney and lungs show that one of his tumours has shrunk and two others have not shown any further growth.

He is no longer taking the drugs and is being monitored every 12 weeks with scans.

Mr Waite said his daughters have teased him about being a guinea pig – and considered buying him some hay.

“I’m a very upbeat sort of bloke and I’ve been very lucky,” he says.

“I feel very privileged to have had the opportunity to go on the trial.”

As yet, nivolumab has only been approved for treating skin cancer and in June it became one of the fastest medicines ever approved for NHS use, in combination with ipilimumab, for the same cancer.

Nivolumab and ipilimumab both work by interrupting the chemical signals that cancers use to convince the immune system they are healthy tissue.

‘Extend life’

Prof Kevin Harrington of the Institute of Cancer Research and consultant at the Royal Marsden Hospital in London, who led the head and neck cancer trial, said nivolumab could be a real “game changer” for patients with advanced head and neck cancer.

“This trial found that it can greatly extend life among a group of patients who have no existing treatment options, without worsening quality of life.

“Once it has relapsed or spread, head and neck cancer is extremely difficult to treat. So it’s great news that these results indicate we now have a new treatment that can significantly extend life, and I’m keen to see it enter the clinic as soon as possible.”

Prof Paul Workman, chief executive of The Institute of Cancer Research, said nivolumab was one of a new wave of immunotherapies that were beginning to have an impact across cancer treatment.

He added: “We hope regulators can work with the manufacturer to avoid delays in getting this drug to patients who have no effective treatment options left to them.”

To view the original of this article CLICK HERE

Regards,
Greg_L-W.

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What Is Immunotherapy? The Basics on These Cancer Treatments

What Is Immunotherapy? The Basics on These Cancer Treatments
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Posted by:
Greg Lance – Watkins
Greg_L-W

eMail: Greg_L-W@BTconnect.com

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Hi,

What Is Immunotherapy? The Basics on These Cancer Treatments

By DENISE GRADY and ANDREW POLLACKJULY 30, 2016


A nurse prepared an immunotherapy drug
at the University of Texas M.D. Anderson Cancer Center in Houston.

Credit Ilana Panich-Linsman for The New York Times

Some of the most promising advances in cancer research in recent years involve treatments known as immunotherapy. These advances are spurring billions of dollars in investment by drug companies, and are leading to hundreds of clinical trials. Here are answers to some basic questions about this complex and rapidly evolving field.
What is immunotherapy?

Immunotherapy refers to any treatment that uses the immune system to fight diseases, including cancer. Unlike chemotherapy, which kills cancer cells, immunotherapy acts on the cells of the immune system, to help them attack the cancer.

What are the types of immunotherapy?

Drugs called checkpoint inhibitors are the most widely used form of immunotherapy for cancer. They block a mechanism that cancer cells use to shut down the immune system. This frees killer T-cells — a critically important part of the immune system — to attack the tumor. Four checkpoint inhibitors have been approved by the Food and Drug Administration and are on the market. They are given intravenously.

Another form of immunotherapy, called cell therapy, involves removing immune cells from the patient, altering them genetically to help them fight cancer, then multiplying them in the laboratory and dripping them, like a transfusion, back into the patient. This type of treatment is manufactured individually for each patient, and is still experimental.

Bispecific antibodies are an alternative to cell therapy, one that does not require individualizing treatment for each patient. These antibodies are proteins that can attach to both a cancer cell and a T-cell, that way bringing them close together so the T-cell can attack the cancer. One such drug, called Blincyto, has been approved to treat a rare type of leukemia.

Vaccines, another form of immunotherapy, have had considerably less success than the others. Unlike childhood vaccines, which are aimed at preventing diseases like measles and mumps, cancer vaccines are aimed at treating the disease once the person has it. The idea is to prompt the immune system to attack the cancer by presenting it with some piece of the cancer.

The only vaccine approved specifically to treat cancer in the United States is Provenge, for prostate cancer. Another vaccine, BCG, which was developed to prevent tuberculosis, has long been used to treat bladder cancer. As a weakened TB bacterium, BCG appears to provoke a general immune system reaction that then works against the cancer. Researchers hope that other vaccines may yet be made to work by combining them with checkpoint inhibitors.

Which types of cancer are treated with immunotherapy?

Checkpoint inhibitors have been approved to treat advanced melanoma, Hodgkin’s lymphoma and cancers of the lung, kidney and bladder. The drugs are being tested in many other types of cancer.

So far, cell therapy has been used mostly for blood cancers like leukemia and lymphoma.

Which cancer drugs are checkpoint inhibitors?

The four on the market are:
Yervoy (ipilimumab) and Opdivo (nivolumab), made by Bristol-Myers Squibb;
Keytruda (pembrolizumab), by Merck;
Tecentriq (atezolizumab), by Genentech.

How well does immunotherapy work?

Though immunotherapy has been stunningly successful in some cases, it still works in only a minority of patients. Generally, 20 percent to 40 percent of patients are helped by checkpoint inhibitors — although the rate can be higher among those with melanoma. Some patients with advanced disease have had remissions that have lasted for years. In some cases, combining two checkpoint inhibitors increases the effectiveness. But for some people the drugs do not work at all, or they help just temporarily.

Cell therapy can produce complete remissions in 25 percent to 90 percent of patients with lymphoma or leukemia, depending on the type of cancer. In some cases the remissions can last for years, but in others relapses occur within a year.

What are the side effects?

Checkpoint inhibitors can cause severe problems that are, essentially, autoimmune illnesses, in which the immune system attacks healthy tissue as well as cancer. One result is inflammation. In the lungs it can cause breathing trouble; in the intestine it can cause diarrhea. Joint and muscle pain, and rheumatoid arthritis can also occur, and the immune system can also attack vital glands like the thyroid and pituitary. These reactions are dangerous, but can often be controlled with steroid medicines like prednisone.

Cell therapy can also lead to severe and potentially fatal reactions resulting from the overstimulation of the immune system. The reactions can usually be controlled, but patients may need to be treated in an intensive care unit.
What does immunotherapy cost?

Does insurance cover it?

Checkpoint inhibitors can cost $150,000 a year. Many insurers will pay if the drug has been approved for the type of cancer the patient has. But sometimes there are high co-payments. Patients in clinical trials may get the drugs free.

Manufacturers have not said yet how much they will charge for cell therapies, assuming they win approval and reach the market. But experts expect the price to be as high as a few hundred thousand dollars.

Where can I get immunotherapy?

Any oncologist can prescribe the checkpoint inhibitors that are on the market. Patients with cancers for which the drugs have not been approved may find insurers reluctant to pay, but may be able to get the drugs for free by volunteering for clinical trials.

Cell therapies are available only through clinical trials now. Most of the study sites are major medical centers.

How can I find out about clinical trials in immunotherapy?

Information is available on the Cancer Research Institute website, or by calling 1-855-216-0127 (Monday through Friday, 8:30 a.m. to 6 p.m. E.T.). Another source is ClinicalTrials.gov.

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Assisting The Immune System To Fight Cancer with Examples & Links

Assisting The Immune System To Fight Cancer with Examples & Links
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Steve Cara expected to sail through the routine medical tests required to increase his life insurance in October 2014. But the results were devastating. He had lung cancer, at age 53. It had begun to spread, and doctors told him it was inoperable.

A few years ago, they would have suggested chemotherapy. Instead, his oncologist, Dr. Matthew D. Hellmann of Memorial Sloan Kettering Cancer Center in New York, recommended an experimental treatment: immunotherapy. Rather than attacking the cancer directly, as chemo does, immunotherapy tries to rally the patient’s own immune system to fight the disease.

Uncertain, Mr. Cara sought a second opinion. A doctor at another major hospital read his scans and pathology report, then asked what Dr. Hellmann had advised. When the doctor heard the answer, Mr. Cara recalled, “he closed up the folder, handed it back to me and said, ‘Run back there as fast as you can.’”

Many others are racing down the same path. Harnessing the immune system to fight cancer, long a medical dream, is becoming a reality. Remarkable stories of tumors melting away and terminal illnesses going into remissions that last years — backed by solid data — have led to an explosion of interest and billions of dollars of investments in the rapidly growing field of immunotherapy. Pharmaceutical companies, philanthropists and the federal government’s “cancer moonshot” program are pouring money into developing treatments. Medical conferences on the topic are packed.

All this has brought new optimism to cancer doctors — a sense that they have begun tapping into a force of nature, the medical equivalent of splitting the atom.

“This is a fundamental change in the way that we think about cancer therapy,” said Dr. Jedd Wolchok, chief of melanoma and immunotherapeutics services at Memorial Sloan Kettering.

Hundreds of clinical trials involving immunotherapy, alone or combined with other treatments, are underway for nearly every type of cancer. “People are asking, waiting, pleading to get into these trials,” said Dr. Arlene Siefker-Radtke, an oncologist at the University of Texas M.D. Anderson Cancer Center in Houston, who specializes in bladder cancer.

The immune system — a network of cells, tissues and biochemicals that they secrete — defends the body against viruses, bacteria and other invaders. But cancer often finds ways to hide from the immune system or block its ability to fight. Immunotherapy tries to help the immune system recognize cancer as a threat, and attack it.

Doctors tried a primitive version of immunotherapy against cancer more than 100 years ago. It sometimes worked remarkably well, but often did not, and they did not understand why. Eventually, radiation and chemotherapy eclipsed it.

Researchers are now focused on two promising types of immunotherapy. One creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer and then infusing them back into the bloodstream. This treatment has produced long remissions in a few hundred children and adults with deadly forms of leukemia or lymphoma for whom standard treatments had failed.

The second approach, far more widely used and the one Mr. Cara tried, involves mass-produced drugs that do not have to be tailored to each patient. The drugs free immune cells to fight cancer by blocking a mechanism — called a checkpoint — that cancer uses to shut down the immune system.

Credit Sam Hodgson for The New York Times
“I almost think of my insides as a war zone. The cancer cells are hiding in mountains and caves, and my immune system is keeping them at bay.”

Joanne Sabol 65, registrar at a medical office, East Northport, N.Y.

Diagnosis:
Non-small-cell lung cancer, stage 4.
Treatment:
Chemotherapy, radiation.
After recurrence, immunotherapy with Keytruda from December 2013 until summer 2015.

Side Effects:
Colitis, joint and muscle pain.

Current Status:
Abdominal tumor shrunk by 78 percent, but not gone.

These drugs, called checkpoint inhibitors, have been approved by the Food and Drug Administration to treat advanced melanoma, Hodgkin’s lymphoma and cancers of the lung, kidney and bladder. More drugs in this class are in the pipeline. Patients are clamoring for checkpoint drugs, including one, Keytruda, known to many as “that Jimmy Carter drug” which, combined with surgery and radiation, has left the former president with no sign of recurrence even though melanoma had spread to his liver and brain.

Checkpoint inhibitors have become an important option for people like Mr. Cara, with advanced lung cancer.

“We can say in all honesty to patients, that while we can’t tell them we can cure metastatic lung cancer right now, we can tell them there’s real hope that they can live for years, and for a lot of patients many years, which really is a complete game-changer,” said Dr. John V. Heymach, a lung cancer specialist and chairman of thoracic/head and neck medical oncology at M.D. Anderson.

Yet for all the promise and excitement, the fact is that so far, immunotherapy has worked in only a minority of patients, and researchers are struggling to find out why. They know they have their hands on an extraordinarily powerful tool, but they cannot fully understand or control it yet.
One Patient’s Story

Mr. Cara, an apparel industry executive from Bridgewater, N.J., had non-small-cell lung cancer, the most common form of the disease. The diagnosis shattered what had been an idyllic life: a happy marriage, sons in college, a successful career, a beautiful home, regular vacations, plenty of golf.

In December 2014, he began treatment with two checkpoint inhibitors. They cost about $150,000 a year, but as a study subject he did not have to pay.

These medicines work on killer T-cells, white blood cells that are often described as the soldiers of the immune system. T-cells are so fierce that they have built-in brakes — the so-called checkpoints — to shut them down and keep them from attacking normal tissue, which could result in autoimmune disorders like Crohn’s disease, lupus or rheumatoid arthritis. One checkpoint stops T-cells from multiplying; another weakens them and shortens their life span.

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As the name suggests, checkpoint inhibitors block the checkpoints, so cancer cannot use them to turn off the immune system.

Mr. Cara took drugs to inhibit both types of checkpoints. Every two weeks, he had intravenous infusions of Yervoy and Opdivo, both made by Bristol-Myers Squibb. He had no problems at first, just a bit of fatigue the day after the infusion. He rarely missed work.

But turning the wrath of the immune system against cancer can be a risky endeavor: Sometimes the patient’s own body gets caught in the crossfire. About two months into the treatment, Mr. Cara broke out in a rash all over his arms, back and chest. It became so severe that he had to go off the drugs. A steroid cream cleared it up and he was able to resume treatment — but with only one drug, Opdivo. Doctors stopped the other in hopes of minimizing the side effects.
Credit Sam Hodgson for The New York Times

“I look forward to the rest of my life. I’m just hoping that I stay safe and it works for other people.”
Steve Cara 54, executive in the apparel industry, Bridgewater, N.J.

Diagnosis:
Non-small-cell lung cancer, stage 4.
TreatmentOpdivo and Yervoy for two months, starting in December 2014, then Opdivo alone for eight months, followed by lung surgery.
Side EffectsRashes, fatigue, lung inflammation.
Current StatusWell, active and no signs of cancer.

Checkpoint inhibitors can take months to begin working, and sometimes cause inflammation that, on scans early in treatment, can make it look like the tumor is growing. But Mr. Cara’s first scans, in March 2015, were stunning.

His tumor had shrunk by a third.

By August, more than half of the tumor had vanished. The rash came back, however, and worsened. Steroids worked again, but in October a far more alarming side effect set in: breathing trouble.

Doctors diagnosed pneumonitis, a lung inflammation caused by an attack from the immune system — a known risk of checkpoint drugs. Continuing the treatment posed too great a danger.

Mr. Cara stopped the infusions, but the months of treatment seemed to have transformed his cancer to stage 2 from stage 4, meaning that it was now operable. This spring surgeons removed about a third of his right lung, and discovered that the cancer was actually gone.

“No cancer was seen in any of the tissue they took out,” Dr. Hellmann said. “‘One hundred percent treatment effect,’” he read from the pathology report. “It was pretty cool.”

Immunotherapy had apparently wiped out the disease. “It’s amazing. Unbelievable,” Mr. Cara said.
Have You Received Immunotherapy Treatment for Cancer?

The New York Times would like to hear from doctors and patients who have experience giving or receiving immunotherapy treatment for cancer.

As of now, he needs no further treatment, but he will be monitored regularly. He is back to work, and golf.

“He’s had the best possible response,” Dr. Hellmann said. “I hope that remains permanent. Only time will tell, and I think he’s conscious of that.”

Mr. Cara acknowledged, “Is there something in the back of me that says this thing never goes away, it could come back any time? Sure. But it’s not the main thing I think. I’m young, I’m strong, I’m healthy, my pathology report came back clean.”

He considered framing that pathology report.

But, he said, “I don’t want to jinx myself.”
Drugs Help Some, but Not Others

When checkpoint inhibitors work, they can really work, producing long remissions that start to look like cures and that persist even after treatment stops. Twenty percent to 40 percent of patients, sometimes more, have good responses. But for many patients, the drugs do not work at all. For others, they work for a while and then stop.

The vexing question, and the focus of research, is, why?

One theory is that additional checkpoints, not yet discovered, may play a role. The hunt is on to find them, and then make new drugs to act on them.

Despite the gaps in knowledge, checkpoint inhibitors are coming into widespread use and are being tried in advanced types of cancer for which standard chemotherapy offers little hope.

Attacking Cancer Cells

Doctors are using immunotherapy to help the cells of the immune system recognize and attack cancer cells.

 

ILLUSTRATION >1<
T-CELL

T-cells are a type of white blood cell that can identify and kill infected, damaged or cancerous cells. Each T-cell has clawlike receptors on its surface that can recognize and lock onto antigens, foreign or abnormal protein fragments on the surface of infected or cancerous cells.

ILLUSTRATION >2<
ACTIVATING A T-CELL

The T-cell must be activated before it can find and attack cancer cells. A specialized cell presents the T-cell with an antigen from a cancer cell, along with a co-stimulator protein. The T-cell begins to hunt down and kill any cells that are covered with the same antigen.

ILLUSTRATION >3<
CANCER & CHECKPOINTS

Cancer cells can avoid destruction by taking advantage of a switch on the T-cell called an immune checkpoint. The checkpoint can shut down the T-cell and suppress the immune response, allowing the cancer to grow undisturbed.

ILLUSTRATION >4<
CHECKPOINT INHIBITORS

Drugs known as checkpoint inhibitors can physically block the checkpoint, which frees the immune system to attack the cancer. A single T-cell can kill thousands of cancer cells. Four checkpoint inhibitors have been approved by the Food and Drug Administration.

One example is anal cancer, a painful disease that carries a stigma because it is often linked to the sexually transmitted human papillomavirus or HPV, which also causes cervical cancer.

Lee, 59, who asked that her last name be withheld to protect her privacy, found out in 2014 that she had the disease, and that it had spread to her liver.

“I was told I’d be dead in 12 to 18 months with treatment, six months with no treatment,” she said.

Chemotherapy and radiation at a hospital near Dallas brought a remission that lasted only a few months. The cancer spread to her lungs.

Bedridden and in severe pain, she entered an immunotherapy trial at M.D. Anderson. In May 2015 she began receiving Opdivo every two weeks. The tumors in her liver and lungs have shrunk by about 70 percent. She is back at work.

While the drugs initially were given only to people with advanced disease, especially those who had little to lose because chemotherapy had stopped working, Dr. Heymach of M.D. Anderson predicted that soon some patients — including some with earlier stages of lung cancer — will receive checkpoint inhibitors as their first treatment.

Immunotherapy is also enabling doctors to help patients in unexpected ways.

Until recently, surgeons were reluctant to operate on people with advanced cancer because they knew from experience that it would not lengthen the patient’s life. But checkpoint inhibitors are changing that. For instance, some patients have taken checkpoint inhibitors for an advanced cancer that had spread around the body, and wound up with only one stubborn tumor left. They then have had it surgically removed and have gone years without a relapse.

“Time has slowed down to the point where you can pay attention to individual tumors, since you’re not running to put out the fire of wholesale systemic progression,” Dr. Wolchok said.

If there is a potential downside to the advances, Dr. Hellmann said, it is that the buzz about immunotherapy has led some patients to think chemotherapy is passé.

Credit Brandon Thibodeaux for The New York Times
“I’m not ready to go. I’m going to hold my head up high and battle this thing.”
Lee 59, business executive, Dallas

Diagnosis:
Anal cancer, stage 4, with spread to lymph nodes, liver and lungs.
TreatmentChemotherapy, radiation. Then, checkpoint inhibitor Opdivo every two weeks since May 2015.
Side Effects: Slight fatigue.
Current Status: Feeling well. Her tumors have shrunk.

“Immunotherapy represents a hugely important new tool, but chemotherapy can work too and has been the backbone of the way we’ve treated patients with lung cancer,” he said. “Immunotherapy is not a replacement for that. It’s a new weapon.”

One of his patients, a 60-year-old man with lung cancer that had spread to his brain, was eager to try immunotherapy instead of chemotherapy. After having radiation treatment for one brain tumor, he began treatment with two checkpoint inhibitors.

But they did not work. So his doctors switched to chemotherapy. “He’s had a tremendous response,” Dr. Hellmann said.

He said it was impossible to tell whether the immunotherapy could have had some delayed effect and worked synergistically with the chemotherapy. Clinical trials are now trying to resolve that question.

But the potential for dangerous side effects cannot be overemphasized, doctors say. A 2010 article in a medical journal reported that a few melanoma patients had died from adverse effects of Yervoy.

In addition to causing lung inflammation, checkpoint inhibitors can lead to rheumatoid arthritis and colitis, a severe inflammation of the intestine — the result of an attack by the revved-up immune system that over-the-counter remedies cannot treat. Patients need steroids like prednisone to quell these attacks. Fortunately — and mysteriously, Dr. Wolchok said — the steroids can halt the gut trouble without stopping the immune fight against the cancer. But if patients delay telling doctors about diarrhea, Dr. Wolchok warned, “they could die” from colitis.

Checkpoint inhibitors can also slow down vital glands — pituitary, adrenal or thyroid — creating a permanent need for hormone treatment. Mr. Cara, for instance, now needs thyroid medication, almost certainly as a result of his treatment. Doctors have reported that a patient with a kidney transplant rejected it after taking a checkpoint inhibitor to treat cancer, apparently because the drug spurred his immune system to attack the organ.

Another of Dr. Hellmann’s lung-cancer patients, Joanne Sabol, 65, had to quit a checkpoint inhibitor because of severe colitis. But she had taken it for about two years, and it shrank a large abdominal tumor by 78 percent. Patients like her are in uncharted territory, and doctors are trying to decide whether to operate to remove what is left of her tumor.

“I have aggressive cancer, but I’m not giving in to it,” Ms. Sabol said. “It’s going to be a big battle with me.”

Coley’s Toxins

Dr. William B. Coley, an American surgeon born in 1862, is widely considered the father of cancer immunotherapy. But he practiced a crude form of it, without understanding how it worked.

Distressed by the painful death of a young woman he had treated for a sarcoma, a bone cancer, in 1891, Dr. Coley began to study the records of other sarcoma patients in New York, according to Dr. David. B. Levine, a medical historian and orthopedic surgeon.

One case leapt out at him: a patient who had several unsuccessful operations to remove a huge sarcoma from his face, and wound up with a severe infection, then called erysipelas, caused by Streptococcal bacteria. The patient was not expected to survive, but he did — and the cancer disappeared.

Helen Coley Nauts, left, rekindled interest in the work of her father, William B. Coley, right, who is considered the father of cancer immunotherapy. Anton Chekhov, center, the Russian physician and playwright, saw a connection between bacterial infections and cancer remission.
Credit Left to right: Cancer Research Institute, Bettmann, via Getty Images, Cancer Research Institute

Dr. Coley found other cases in which cancer went away after erysipelas. Not much was known about the immune system, and he suspected, mistakenly, that the bacteria were somehow destroying the tumors. Researchers today think the infection set off an intense immune response that killed both the germs and the cancer.

Dr. Coley was not alone in believing that bacteria could fight cancer. In a letter to a colleague in 1890, the Russian physician and playwright Anton Chekhov wrote of erysipelas: “It has long been noted that the growth of malignant tumors halts for a time when this disease is present.”

Dr. Coley began to inject terminally ill cancer patients with Streptococcal bacteria in the 1890s. His first patient, a drug addict with an advanced sarcoma, was expected to die within weeks, but the disease went into remission and he lived eight years.

Dr. Coley treated other patients, with mixed results. Some tumors regressed, but sometimes the bacteria caused infections that went out of control. Dr. Coley developed an extract of heat-killed bacteria that came to be called Coley’s mixed toxins, and he treated hundreds of patients over several decades. Many became quite ill, with shaking chills and raging fevers. But some were cured.

Parke-Davis and Company began producing Coley’s toxins in 1899, and continued for 30 years. Various hospitals in Europe and the United States, including the Mayo Clinic, used the toxins, but the results were not consistent.

Early in the 20th century, radiation treatment came into use. Its results were more predictable, and the cancer establishment began turning away from Coley’s toxins. Dr. Coley’s own institution, Memorial Hospital (now Memorial Sloan Kettering Cancer Center) instituted a policy in 1915 stating that inpatients had to be given radiation, not the toxins. Some other hospitals continued using them, but interest gradually waned. Dr. Coley died in 1936.

Chemotherapy, developed after World War II, was another blow to his methods. And in 1965, the American Cancer Society added Coley’s toxins to its list of “unproven” treatments. (The toxins were later taken off the list.)

After Dr. Coley’s death, his daughter, Helen Coley Nauts, studied some 800 case records that he had left behind, and became convinced that he was onto something important. She tried to rekindle interest in his work, but she was thwarted by doctors who opposed it, including some with high rank at Sloan Kettering. However, in 1953 she founded the Cancer Research Institute in New York, a nonprofit that has become a significant supporter of research on the interplay between cancer and the immune system. The group awarded more than $29.4 million in scientific grants in 2015, and its advisory board includes Dr. Wolchok and the scientist credited with developing the first checkpoint inhibitor, James P. Allison.

Dr. James P. Allison and Dr. Padmanee Sharma have been research collaborators since 2005, and spouses since 2014. Dr. Allison developed Yervoy, the first of the checkpoint inhibitors.
Credit Ilana Panich-Linsman for The New York Times

The Scientist and the Doctor

“Are you Dr. Allison?”

James Allison and his wife, Dr. Padmanee Sharma, had just settled into their airplane seats when another passenger approached with tears in her eyes and thanked him for creating the drug that was keeping her husband alive. Dr. Sharma described the encounter during a joint interview with her and Dr. Allison in his office at M.D. Anderson in Houston, where both work.

“Every time Jim meets a patient, he cries,” Dr. Sharma said.

“Well, not every time,” Dr. Allison said.

Dr. Allison, 67, and Dr. Sharma, 45, have been research collaborators since 2005, and spouses since 2014, when he proposed by saying that nobody else could stand either of them — they talk about their work all the time — so they might as well get married.

The drug the woman on the plane thanked him for was Yervoy, the first of the checkpoint inhibitors. It was approved for advanced melanoma in 2011. Dr. Allison — a scientist, not a physician — has won numerous research awards and is expected by many to win a Nobel Prize. He drives a Porsche convertible with a license plate bearing the name of the checkpoint he deciphered: CTLA-4.

A bearded, slightly rumpled figure, Dr. Allison plays harmonica with research colleagues in a blues-rock band called the Checkpoints. He is good enough to have accompanied Willie Nelson onstage at the Redneck Country Club in Stafford, Tex., this spring, playing, “Roll Me Up and Smoke Me When I Die.”

Immunology, particularly the study of T-cells, has been his life’s work. Cancer came later. “I became interested in cancer because I’ve lost a number of family members to cancer,” said Dr. Allison, chairman of the immunology department and executive director of the immunotherapy platform at M.D. Anderson. “My mother and two of her brothers, and my own brother, died of cancer.”

Around the time of his brother’s death from prostate cancer, Dr. Allison learned that he had the same disease himself. He was treated successfully, he said, adding with a laugh that he was more likely to die from inactivity than from cancer.

In the 1990s, Dr. Allison, then at the University of California, Berkeley, and Dr. Jeffrey Bluestone of the University of California, San Francisco, independently made a landmark discovery: They proved that a molecule widely believed to activate the immune system actually shut it down. The molecule was a protein on the surface of T-cells — a crucial checkpoint — and it was nature’s way of subduing the T-cells, apparently to dial back their ferocious activity and prevent them from attacking a person’s own tissue. Cancer cells can sometimes lock onto checkpoints, disabling the T-cells.

Dr. Allison wondered if it might be possible to block the checkpoint and launch the T-cells against cancer. He and a postdoctoral fellow, Dana Leach, developed an antibody — a molecule made by certain cells of the immune system — that would stick to the checkpoint and block it. When the researchers gave the antibody to mice with cancer, tumors vanished.

Recalling those first tests in mice, Dr. Allison said it was astounding to see the cancers shrink and disappear. Veterinarians thought the mice had contracted an infection or a skin disease. But the sores that worried the vets were actually tumors that were ulcerating and rotting away under assault by T-cells.

Many drug companies were skeptical about the findings, but one, Medarex, created a human version of the antibody. Medarex was later acquired by Bristol-Myers Squibb, and the antibody, given the trade name Yervoy, was approved in 2011 to treat advanced melanoma.

Credit Mark Makela for The New York Times

“I believe I have good odds it’s going to work. If it doesn’t, I’ll look for another trial.”
Brian Raditz
62, clinical psychologist, Merion, Pa.

Diagnosis:
Prostate cancer, stage 4.
Treatment:
Surgery, radiation, hormones. After recurrence, the vaccine Provenge and the checkpoint inhibitor drug Yervoy.

Side EffectsRashes, fatigue.

Current Status:
Not in remission, but not progressing.

It became the first drug to prolong survival in people with this deadly form of cancer. Major studies that started before it was approved found that among 1,861 patients treated for advanced disease, about 22 percent were still alive three years later, with no signs of recurrence — an astounding result for a disease that was almost always fatal. Some have survived 10 years or longer.

The discoveries that led to the drug, Dr. Allison said, came entirely from years of basic research in immunology — experiments in test tubes and mice — and not from the clinical or “translational” science, aimed at moving rapidly into humans, that is so heavily favored now by institutions that pay for studies.

“None of this came from cancer research, none,” Dr. Allison said, adding that without support for basic research, “progress, if any, will be incremental, not a big leap.”

His own work is well funded, he said, but he worries about an overall trend to shortchange basic science.

The focus of much of his and Dr. Sharma’s research now is to understand how and why checkpoint inhibitors work in some patients and not others.

Dr. Sharma, a professor of genitourinary medical oncology, is a physician and researcher who treats patients and oversees clinical trials, and she brings stories home to Dr. Allison about patients whose lives may be extended by his discoveries.

In general, checkpoint inhibitors seem to work best for tumors with many mutations, like most melanomas and cancers of the lung and bladder.

“It’s like buying a lottery ticket,” Dr. Sharma said. “The more genetic abnormalities, the more lottery tickets you’ve bought — and you have a much higher chance of a T-cell recognizing something to start the immune response.”

One area of particular interest is the tissue immediately in and around a tumor, what researchers call the microenvironment. By examining that zone, scientists can tell whether T-cells are fighting the cancer. Sometimes T-cells mob the margins of a tumor, but cannot get in. Other times, they get in but cannot kill it.

“How do we understand what drives the immune response in one patient to give a good clinical outcome, and how do we then drive that same immune response in all the other patients?” Dr. Sharma asked. “Did the T-cells get in? If not, is there another drug that can drive the T-cells in?”

Researchers also suspect that checkpoint inhibitors might work better if combined with treatments that kill tumor cells, because debris from dead cancer cells may help the immune system recognize its target. Studies are underway to test checkpoint drugs in combination with cell-killing treatments like chemotherapy and radiation. But it is a delicate balance to adjust the timing and doses, because in addition to killing cancer cells, those other treatments can knock out the immune system just when it is needed most.

David Wight with his daughter Isabella after a soccer game in Anchorage, Alaska. “I’m very fortunate,” he said.
Credit Joshua Corbett for The New York Times

Flying 3,300 Miles for Treatment

As word spreads about immunotherapy, a troubling fact remains: Patients do not have equal access to the new treatments, which can be prohibitively expensive. Insurers cover F.D.A.-approved treatments, but co-payments can be high for costly drugs. Some people get costs covered by volunteering for clinical trials that are testing new drugs or novel combinations. But not everyone can, or wants to, enter a study. Participants tend to have the education, determination and means required to get second and third opinions, rearrange their lives, and buy plane tickets to get to cutting-edge medical centers. And they are willing to take risks for a chance to survive. Minorities have been underrepresented in studies, for reasons that are not clear.

David Wight, a retired oil engineer in Anchorage, is a study participant who has been able to take every possible step to save his life. When bladder cancer began to spread in his abdomen, he was given three to 12 months to live. That was four and a half years ago.

On a recent Saturday, Mr. Wight, who is 75 but looks younger, refereed a boys’ soccer game, racing up and down the field with the players. The following Wednesday he rose at 3 a.m. to fly 3,300 miles to Houston, where he would arrive at about 5 p.m. He has been making that trip every other week for over two years to receive immunotherapy at M.D. Anderson. For about a year and a half, his disease has been in complete remission.

Until recently, he paid his own airfare. But a few months ago, Bristol-Myers Squibb, the maker of the drug being studied, began picking up the tab, even reimbursing him retroactively — about $50,000 so far.

He has five children: three in their 40s, a son, 16, and a daughter, 10. The younger two were only 10 and 5 when he learned he was ill, and the thought that he might not have survived to raise them still brings tears to his eyes. Describing the time he has gained to be with his family, he said, “I won a lottery that’s bigger than anybody could imagine.”

His cancer was diagnosed in summer 2010, after a test during a routine physical found cancer cells in his urine. A small tumor had invaded the wall of his bladder. Mr. Wight had his bladder removed at a hospital in Anchorage, and was told he needed no further treatment.

A year after the surgery, he and his doctors were horrified to find that a large tumor had wrapped itself around his colon. Only then did the doctors discover that he had a rare, aggressive type of bladder cancer, called plasmacytoid. His doctors consulted with a hospital in Seattle, which devised a treatment plan.

“They said one word that told me I was not where I wanted to be: ‘palliative,’” Mr. Wight said. He knew palliative treatment was meant to ease symptoms, but not cure the disease. “I said, ‘No thank you. We can do better than that,’” he recalled.

His next stop was M.D. Anderson. Months of chemotherapy shrank the tumor enough to allow colon surgery in May 2012. But the disease kept coming back: spots in one lung, then the other, then a tumor under his kidney.

Credit Ilana Panich-Linsman for The New York Times

“Never give up. If one thing doesn’t work, look for something else. Give it your best shot.”
David Wight
75, retired engineer, Anchorage, Alaska

Diagnosis:
Bladder cancer, plasmacytoid variant, stage 4.
Treatment:
Opdivo, every two weeks since June 2014.
He also received Yervoy for the first three months of therapy.
Side Effects: Itching.

Current Status:
Well, active and disease in remission for more than a year.

“I was getting a new tumor every six to eight months,” he said.

Chemotherapy and an experimental gene therapy cleared his lungs and shrank the tumor near his kidney but could not get rid of it.

In June 2014, Mr. Wight became one of the first patients with bladder cancer at M.D. Anderson to enter a study of two checkpoint inhibitors. For three months he received Yervoy and Opdivo every two weeks, and then continued with only Opdivo.

The tumor under his kidney shrank, then disappeared. It has been gone for a year and a half, and he has had no other signs of cancer. He is still receiving Opdivo — the reason for his regular trips to Houston.

“I’m very fortunate,” Mr. Wight said. “It has for me a single irritating side effect. It makes me itch like you wouldn’t believe. I itch all the time but it’s a small price to pay to stay alive and be feeling pretty well.”

An antihistamine helps. Regarding how long he will keep being treated, he said: “It’s experimental. You don’t know the answer. As long as I have positive results I’m eligible for the treatment.”

His oncologist, Dr. Siefker-Radtke, called his response to immunotherapy “fantastic” and said other patients, also in complete or partial remission, were flying or driving to Houston for treatments every two or three weeks. Many do not want to stop taking the drugs.

But doctors do not know how long the treatments should continue. They wonder how long the remissions will last, and whether some will even turn out to be cures, Dr. Siefker-Radtke said. Some studies were planned to last just a year or two, longer than the life expectancy of most patients with advanced disease. Researchers did not think they would have to decide whether to keep treating people for years.

“We were not expecting to see patients going this long,” Dr. Siefker-Radtke said.

Credit Ilana Panich-Linsman for The New York Times
“My energy is good. I feel O.K., I live by myself and I’m independent, thank God. Without this treatment, I’d probably be dead.”
Howard Burgner 73, retired federal employee, Houston

Diagnosis:
Acute myeloid leukemia, resistant to chemotherapy. Median survival, four to six months.
TreatmentImmunotherapy with Opdivo and chemotherapy with azacytidine since July 2015.

Side Effects:
Thirst, occasional constipation.

Current Status:
Improved and stable, but disease not in remission.

To view the original CLICK HERE

Related Coverage

A Breakthrough Against Leukemia Using Altered T-Cells DEC. 9, 2012
T-Cell Therapy Puts Leukemia Patients in Extended Remission OCT. 15, 2014
Cell Therapy Promising for Acute Type of Leukemia MARCH 20, 2013

Immune System, Loaded With Remade T-cells, Vanquishes Cancer SEPT. 12, 2011
F.D.A. Allows First Use of a Novel Cancer Drug SEPT. 4, 2014
New System for Treating Cancer Seen as Hopeful JUNE 2, 2014
Breaking Through Cancer’s Shield OCT. 14, 2013
F.D.A. Approves an Immunotherapy Drug for Bladder Cancer MAY 18, 2016

 

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Chimeric Antigen Receptor T-Cell Therapy for Cancer

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Chimeric Antigen Receptor T-Cell Therapy

Tumor-targeting T-cell therapies are generating remarkable remissions in hard-to-beat cancers—and attracting millions of dollars of investment along the way.

By Vicki Brower | April 1, 2015

 
BUILDING A BETTER T-CELL: By modifying T cells to express chimeric antigen receptors (CARs) that recognize cancer-specific antigens, researchers can prime the cells to recognize and kill tumor cells that would otherwise escape immune detection. The process involves extracting a patient’s T cells, transfecting them with a gene for a CAR, then reinfusing the transfected cells into the patient.© LUCY READING-IKKANDALast December, scientists at Juno Therapeutics reported at the American Society of Hematology (ASH) meeting that, in an ongoing Phase 1 trial, its chimeric antigen receptor (CAR) T-cell therapy, JCAR015, put 24 of 27 adults with refractive acute lymphoblastic leukemia (ALL) into remission, with six patients remaining disease free for more than a year (ASH 2014, Abstract 382, 2014). This disease is extremely hard to treat and progresses rapidly when it becomes refractory; most patients die within a few months. “This response rate is unprecedented for patients who had stopped responding to all other treatments,” says Michel Sadelain, a founding director of Memorial Sloan Kettering’s Center for Cell Engineering and a cofounder of Juno.
Founded just a year earlier, the Seattle-based company now has four CD19-targeting CAR T-cell therapies in trials. The premise is simple: extract a patient’s T cells from blood and train them to recognize and kill cancer by modifying them with a viral vector to express an artificial, or chimeric, receptor specific for a particular cancer-associated antigen—in this case, CD19, an antigen expressed in  B-cell–related  blood cancers—then reinfuse the cells back into the patient. (See illustration at left.) The engineered cells recognize and kill cancerous cells, while reactivating other immune players that have been dampened by cancer’s inhibitory signals. “CAR therapy is at the same time cell therapy, gene therapy, and immunotherapy,” says Sadelain. “It represents a radical departure from all forms of medicine in existence until now.” Promising preclinical results have moved Juno’s CD19 therapies into trials for ALL, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia (CLL), and the company has three more CAR T-cell immunotherapies for a number of solid cancers close behind.

A few weeks after the ASH meeting, Juno went public for a whopping $264.6 million, the largest biotech initial public offering (IPO) of 2014. Within a month, the company’s valuation rose from $2 billion to $4.7 billion, the largest among biotechs in a decade. By the end of 2016, the company plans to have 10 drug trials for six diseases up and running using CAR T cells produced in a brand-new manufacturing facility.

And Juno is not alone. This relatively new sector is experiencing a frenzy of scientific activity, corporate partnering, and financing that took off in late 2013, continued throughout 2014, and moved straight into the new year with no sign of letting up. By now, most major pharmaceutical companies have jumped into the CAR T-cell arena. In the past two years alone, at least half a dozen companies have made deals worth hundreds of millions of dollars up front, with much more expected in the future as products move through the pipeline. (See chart below.) This influx of funding is now supporting dozens of clinical trials.

While most of these studies are currently aimed at late-stage disease for which other therapeutic options have failed, researchers in the field anticipate that these immunotherapies could replace standard cancer treatments in the future. “While we are evaluating these therapies in advanced cancer now, we absolutely believe that they have the potential to become frontline therapies,” Sadelain says.

Long time coming

CAR T-cell therapy has had a lengthy run-up to what may appear to be overnight success. The first CAR T cells were developed at the Weizmann Institute of Science in Israel in the late 1980s by chemist and immunologist Zelig Eshhar. In 1990, Eshhar took a year-long sabbatical to join Steven Rosenberg at the National Institutes of Health, where they prepared CARs that targeted human melanoma. “We designed CAR T cells to overcome a number of problems in getting T cells to attack cancer,” says Eshhar. These problems included a tumor’s ability to escape immune recognition by silencing the major histocompatibility complex molecules and the generally immunosuppressive tumor microenvironment.


NEW AND IMPROVED CARs: Zelig Eshhar and Steven Rosenberg constructed the first CAR T cells using a modular design, including a specific cancer-targeting antibody outside the cell, a transmembrane component, and an intracellular costimulatory signaling domain that amplifies the activation of the CAR T cells. Second- and third-generation CAR T-cell technologies have added additional costimulatory domains within the cells, as well as additional receptors to improve targeting of the T-cell attack and minimize side effects.
© LUCY READING-IKKANDA

Eshhar and Rosenberg constructed the CAR T cells with a modular design that included a specific cancer-targeting antibody, and later added a costimulatory signaling domain that amplifies the activation of the cells, giving them a stronger signal to multiply and kill cancer cells. Since that early work, researchers in both academia and industry have developed and tweaked each section of the modular design. (See illustration above.) “Ultimately, we needed 20 years to learn how to supercharge these cells to deliver anticancer activity,” says Arie Belldegrun, president and CEO of Kite Pharma in Santa Monica, California, which is assessing CAR T cells in six trials for B cell leukemia and lymphomas, and glioblastoma. Eshhar, a member of Kite Pharma’s scientific advisory board, continues to collaborate with Rosenberg, who serves as a special advisor to the company.

Juno is now working on two second-generation CAR technologies that incorporate mechanisms to further amplify T-cell activation or to dampen it, in the case of adverse reactions. (See “Safety concerns.”) These so-called “armored” chimeric antigen receptors are designed to combat the inhibitory tumor microenvironment by incorporating a signaling protein such as IL-12, which stimulates T-cell activation and recruitment. Juno believes “armored CAR” technology will be especially useful for solid tumors, whose microenvironment and potent immunosuppressive mechanisms can make raising antitumor responses more challenging.

Like Juno, Houston, Texas–based Bellicum Pharmaceuticals is working on refinements for next-generation CAR T-cell treatments. To better control antigen activation by its CAR T cells, for example, Bellicum is separating its dual costimulatory domain from the antigen-recognition domain, moving it onto a separate molecular switch that can be controlled by the small-molecule drug rimiducid. These T cells, known as GoCAR-Ts, can only be fully activated when they are exposed to both cancer cells and the drug.

In addition to altering the components of the CAR T cells themselves, researchers are also experimenting with different methods to introduce the receptors into the patients’ cells. At MD Anderson Cancer Center in Houston, Laurence Cooper and his colleagues are using a nonviral system called “Sleeping Beauty,” licensed from the University of Minnesota’s Perry Hackett, that relies on a transposon derived from fish to paste any desired gene into the genome. “This system employs electroporation [an electric current] to introduce elements of the Sleeping Beauty system into T cells,” says Cooper, who hopes the system will be less complex and cheaper to use than viral vectors.

While CAR T cells are being tested first as monotherapies, researchers are also giving thought to how best to use CAR T cells with other immunotherapies in the future. “We are excited about combining checkpoint inhibitors such as PD-1 [programmed death-1] inhibitors and anti-CTLA4 [anti-cytotoxic T-lymphocyte antigen 4] drugs with CAR T cells,” Eshhar says.

A frenzy of deal making

Over the past few years, the industry has been a hive of activity, with a half dozen companies forging deals valued at more than a half billion dollars in total. In addition to the perceived financial potential of these therapies, the feeding frenzy may in part be attributable to the fact that regulatory authorities are giving CAR T-cell treatments priority review for filling unmet medical needs. Many of these therapies are receiving orphan or breakthrough status from the US Food and Drug Administration (FDA), bringing expedited regulatory review, which translates into earlier realization of financial benefits from more rapid market entry. In November 2014, for example, the FDA granted orphan status to Juno’s JCAR015. Kite’s KTE-C19 for refractory aggressive non-Hodgkin’s lymphoma also recently received the designation from both the FDA and the European Medicines Agency. And the University of Pennsylvania /Novartis’s CTL019 for ALL received breakthrough status last July.

CAR T-CELL DEALS

Institution/Company Date Partner Terms
University of Pennsylvania August 2012 Novartis Undisclosed
Celgene March 2013 Bluebird Bio, Baylor College of Medicine Unspecified upfront payment plus up to $225 million per product in option fees and milestone payments
Cellectis June 2014 Pfizer $80 million upfront plus up to $185 million per product and royalties
Cellectis January 2015 Ohio State University Undisclosed
Kite Pharma January 2015 Amgen $60 million upfront and up to $525 million per product in milestone payments, plus royalties on sales and IP licensing
Md Anderson January 2015 Ziopharm, Intrexon $100 million in stock and $15–20 million/year for 3 years

A new report by EP Vantage, the editorial team at life science market intelligence firm Evaluate Ltd, notes that while investor enthusiasm for this sector is unlikely to diminish anytime soon, “there may be hidden dangers” for those in it to make a big return. “CAR T therapy looks like it’s becoming little short of a revolution in the treatment of some cancer types, but numerous risks are being lost in the hype,” writes report author Jacob Plieth, a biochemist by training. “It is important to appreciate the risks as well as the opportunities to have a clear understanding of the market potential of these therapies and their developers.”

Clinical results spark hope

In 2011, the Penn group described the results of an early trial of its CTL019 CAR T-cell treatment in three advanced chronic lymphocytic leukemia (CLL) patients (Sci Transl Med, 3:95ra73, 2011). The findings—including two patients who have now remained in remission 4.5 years after their treatment—served as an early demonstration that CAR T cells can successfully treat patients with late-stage disease. The team has now tested CAR T-cell therapies in about 125 people, with six different trials underway for pediatric and adult ALL, CLL, multiple myeloma, and non-Hodgkin’s lymphoma. Other CAR T-cell therapies are in trials for solid tumors, including ovarian, breast, and pancreatic cancers, and mesothelioma and glioblastoma.

CAR T-CELL BIOTECH IPOs

Company Date Value
Kite Pharma June 2014 $134.1 million
Bellicum December 2014 $160 million
Juno December 2014 $264.6 million
Cellectis March 2015 $228 million

“One of the exciting things about these cells is that they expand to high numbers and maintain long-term functional persistence,” says David Porter, a leukemia specialist and director of blood and marrow transplantation at Penn.

In a recent Penn study of 30 children and adults with relapsed or refractory ALL who received CTL019, 90 percent achieved total remission, and 78 percent were still living at the end of the study two years later (NEJM, 371:1507-17, 2014). Moreover, “very few patients—three—got a bone marrow transplant after CTL019, suggesting that this could be a replacement for bone marrow transplant and not just a bridge to transplant,” added senior author Stephan Grupp, director of translational research for the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia.

At ASH, Grupp discussed a follow-up study, including 39 pediatric patients, which showed a 92 percent complete remission rate following CTL019 treatment. Of those, 76 percent remain in complete remission after six months (ASH 2014, Abstract 380, 2014). “The first ALL patient treated is still in remission nearly three years later,” says Grupp. In September, Novartis pledged $20 million to build a Center for Advanced Cellular Therapeutics to manufacture CAR T cells on the Penn campus, to be completed next year. Penn is now conducting pilot trials aimed at solid tumors, including mesothelioma; ovarian, breast, and pancreatic cancers; and glioblastoma.

A team at the National Cancer Institute, including Rosenberg, has also reported successes with CAR T cell therapy, focusing on patients with refractory diffuse large B-cell lymphoma, an aggressive disease for which survival without treatment is measured in months. Following treatment with CD19-targeting T cells, 22 of 27 patients had either complete or partial remissions; 10 have remained cancer free for up to 37 months (ASH 2014, Abstract 550, 2014). These and other trials have demonstrated that CAR T-cell therapies can successfully treat leukemias and lymphomas in some patients for whom there are no other treatments.

There are currently many other CAR T-cell trials underway in leukemia and lymphoma, and more beginning in the near future. Scientists in this arena are energized by these and other results, and many see CAR T-cell therapies as the future of cancer treatment. “I believe these trials indicate that chemotherapy may be on its way out,” says MD Anderson’s Cooper.

Vicki Brower is a freelance science writer living in New York City.

SAFETY CONCERNS
Despite the growing number and length of remissions using CAR T-cell therapy to treat leukemias and lymphomas, key challenges remain—first and foremost, safety. There have been a half-dozen treatment-related deaths in the University of Pennsylvania and Juno trials in the past few years that involve a major side-effect of CAR T-cell therapy called cytokine-release syndrome (CRS). T-cell activation causes the release of inflammatory cytokines, producing symptoms including high fevers, aches, hypotension, and, more rarely, pulmonary edema and neurologic effects such as delirium.

Researchers tie the severity of what they call a “cytokine storm” to tumor burden—a patient’s total mass of cancer tissue or quantity of malignant cells. One hypothesis for this is that higher tumor burden seems to incite a stronger immune reaction. Moreover, the deaths have all occurred in adults, some of whom had serious underlying medical issues, and others who had undiagnosed infections. Interestingly, children seem relatively resistant to severe CRS and, when they get it, are more easily managed, says Michel Sadelain of Memorial Sloan Kettering and Juno. “Adults do not tolerate the treatment as well as children, in whom the cells differ in speed of action and persistence,” Sadelain says. Treatment with an anti-IL6 antibody, or in severe cases, corticosteroids, can mitigate a cytokine storm’s severity, as can dosing with lower numbers of CAR T cells.

“In our trial [on diffuse large B-cell lymphoma], we saw that toxicity was reduced in patients who received low-dose chemotherapy rather than high-dose [prior to CAR T-cell treatment], and lower numbers of engineered T cells [than given previously],” says James Kochenderfer of the National Cancer Institute (NCI).

Bellicum is partnering with the University of Leiden in the Netherlands and the NCI, among others, to develop “suicide switches,” or safety on-and-off switches that are incorporated into CAR T-cell candidates to control T-cell activation and proliferation. And Juno’s second-generation “armored” CAR technologies include mechanisms to dampen T-cell activation. “It will be important to find new ways to overcome toxicity of CAR T cells,” says the Weizmann Institute’s Zelig Eshhar.

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