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Soon after she received the treatment, Karen Koehler’s brain swelled. Her blood pressure plummeted. As she fell into a coma, her husband and sister sat at her bedside — urging the doctors to keep pushing her farther along the razor’s edge between life and death.

Koehler was undergoing a promising — and terrifying — experimental therapy that her oncologists hoped could rid her body of cancer entirely. It’s called CAR-T therapy, and it works by engineering the patient’s own immune cells to attack cancer.

One of the hallmarks of CAR-T: It has to nearly kill you if it’s going to save you.


The treatment induces such sudden and severe side effects that it can take a small army of top specialists to keep patients alive while their newly engineered immune systems attack their cancer cells. The result: CAR-T remains so risky, so complex, and so difficult to manage that experts warn it’ll be years before it’s available to most patients who would stand to benefit — even though two drug makers, startup Kite Pharma and pharmaceutical giant Novartis, are racing to get their versions of the therapy approved by the the Food and Drug Administration as early as next year.

“The thing is, cellular therapies are extraordinarily complex drugs,” said Dr. Michael Milone, a CAR-T scientist at University of Pennsylvania.


CAR-T has so far been tested on hundreds of patients, mostly with blood cancers; solid tumors pose more of a challenge. Proponents say it’s just about ready for prime time. But it’s still quite early, cautioned Bruce Levine, a gene therapy professor at University of Pennsylvania. (Both Levine and Milone are working with Novartis on its CAR-T therapy.)

“We’re in the Model T phase,” Levine said.

An infusion of Frankenstein cells

CAR-T therapy, short for chimeric antigen receptor T cell therapy, works like this: Physicians draw a patient’s blood and harvest her cytotoxic T cells — that is, cells that are already circulating in her body and are designed to attack infected or malignant cells. The cells are re-engineered in a lab so they can learn how to attack her particular cancer. The patient is then usually treated with chemotherapy to wipe out some of her existing immune cells, to give the engineered ones more room to replicate.

The therapy itself consists of an infusion: The Frankensteinian T cells are fed back into the patient’s bloodstream, where they proliferate and work furiously to kill tumor cells. A single T cell can wipe out up to 100,000 cells.

But here’s the rub: Adding hyperactive T cells can cause the body’s immune response to go haywire.

Patients often wind up with a condition called cytokine release syndrome, which occurs when T cells excrete huge quantities of cytokines — small proteins involved in cell signaling. A “cytokine storm” can cause severe fevers, nausea, extreme fatigue, difficulty breathing, low blood pressure, and organ swelling.

In other words, it feels like the worst imaginable case of flu — which, of course, can be devastating in a patient already weakened by cancer and chemotherapy.

“The more tumor you have in your body, the more severe the cytokine release syndrome,” Milone said. As the tumors go away, the cytokines go away, and symptoms subside. A number of rudimentary tools are being used to temper the side effects of a CAR-T infusion, including steroids and drugs more typically used to treat juvenile arthritis.

But few physicians have a grip on how to appropriately treat cytokine release syndrome, because it’s so rare in everyday practice, Milone said.

A second complication associated with some CAR-T therapies is neurotoxicity: Patients often experience memory loss, hallucinations, and swelling of the brain. Researchers still don’t know much about what causes the neurotoxicity, but it’s already proven deadly.

Last month, three patients with acute lymphoblastic leukemia enrolled in a Juno Therapeutics CAR-T clinical trial died from complications including neurotoxicity, prompting the FDA to temporarily halt the trial. Juno attributed the deaths in part to one of the chemotherapy drugs, fludarabine, given to patients before they received their infusion of engineered cells. After Juno rewrote the trial protocol to eliminate that drug, the FDA allowed it to restart.

“I think we have made significant progress with cytokine release syndrome,” said Steve Harr, chief financial officer of Juno Therapeutics. “But we have a lot more to do with neurotoxicity.”

Juno now hopes to get its drugs approved as early as 2018.

On their own, cytokine storms and neurotoxicity are both highly dangerous. Karen Koehler was hit with both.

When vomiting is good news

A teacher and avid golfer who lives in New Jersey, Koehler was diagnosed with chronic lymphocytic leukemia in 2011. It’s a form of blood cancer that’s often fairly benign, and for the first few years, doctors advised her to simply keep checking in — no therapy needed.

“I felt healthy, but doctors basically told me I had this nuclear bomb in my body,” said Koehler, who is now 59. “I just didn’t know if or when it would go off.”

Still, she carried on, even naming her blood cancer “Lucy and Ethel,” which has the letters “CLL” in it. But in 2014, her cancer suddenly changed, from seemingly innocuous to terminal. She was told that chemotherapy wouldn’t work in her case, and was given a maximum of two years to live.

Stunned, Koehler began looking for options. A physician told her that an experimental therapy called CAR-T was working wonders for other patients with her specific cancer, and she enrolled in a trial at Memorial Sloan Kettering Cancer Center in New York.

Engineering the cells to infuse them back into the patient can take anywhere from a few days to a few weeks. In Koehler’s case, her blood was drawn in October 2014, and she didn’t receive the therapy until February 2015.

She was fitted with a catheter under her arm on a Friday. On Saturday and Sunday, she was given two days of chemotherapy — a combination of the drugs fludarabine and cytoxan. Koehler didn’t have any reaction at that point.

“The big joke through all of this was how good I looked,” she said. “My husband is bald, so I can’t tell you how many times I was sitting in hospital, and doctors would start talking to him, instead, because he was bald.”

On Tuesday, she got her “bag of cells” infused. It was no big deal, either — she sat there, chatting, as nurses bustled in and out to check her vitals.

An hour later, she started getting sick. She knew it was a sign that her immune system was kicking into overdrive.

“When I started throwing up, I thought, ‘Oh my god, this is great,’” Koehler said.

Then, it wasn’t. Her heart started beating erratically. Her blood pressure dropped. Then brain swelling. Delirium. A coma.

They moved her to the intensive care unit. And that’s where she stayed, for eight days.

Her husband and her sister, a nurse, told the doctor to “take her as far as you can take her,” Koehler said. They didn’t want to stop the process prematurely, and risk not killing all of the cancer.

“But I got to the brink, and they said enough,” Koehler said. Doctors gave her an infusion of steroids, which shuts down the T cells that cause the cytokine storm — and also halts their aggressive attack on the cancer.

When she came to, Koehler just remembers being confused. Thanks, most likely, to the effects of the fludarabine, she had frequent, severe hallucinations. She imagined the nurses were selling blood next door. That she was on a TV show about golf.

“That stuff was scary — I knew the hallucinations were just a bad dream, but they seemed so real,” she said.

All told, Koehler was in the hospital for three weeks. Her costs were covered by insurance and by Juno, since she was part of its clinical trial. But the costs for treating future patients could be enormous, with potential bills running hundreds of thousands of dollars. Harr, the CFO of Juno, has seen estimates as high as $500,000 to $750,000 — though said that doesn’t necessarily reflect how Juno will price its own CAR-T therapy.

Koehler’s hallucinations persisted for several weeks after she left the hospital, as did the confusion.

But the treatment worked: By March 28, she was able to make it down to Florida for a family reunion. She golfed nine holes.

cancer CAR-T
Karen and Dave Koehler are grateful that her experimental CAR-T therapy beat back her cancer. Cancer Research Institute

A ‘suicide switch’ to turn off the therapy

Koehler’s experience shows just how tantalizing CAR-T is: A year and a half after the treatment, she remains free of cancer. Dr. Stephanie Goff, a surgeon at the National Cancer Institute who’s working with Kite on its treatments, said CAR-T seems to work in about half of patients with lymphomas and leukemias who have run out of other treatment options, though some studies suggest the response rate is higher in certain patient populations, such as children with acute lymphoblastic leukemia.

But the side effects Koehler experienced, and the enormous amount of expertise it took to manage them, illustrate the risks of expanding the therapy to a broad patient population. So far, it’s been tested in just a handful of academic hospitals, including the University of Pennsylvania and Memorial Sloan Kettering in New York.

To bring CAR-T mainstream, biotech scientists are working avidly to find ways to minimize side effects.

Houston-based Bellicum Pharmaceuticals, for instance, is designing two switches to help control the deployment of T cells. One is triggered by a drug called rimiducid, which turns on a “suicide switch” in the T cell, causing it to die. The second works more like a gas pedal that can control how fast the cells proliferate in the body and attack the tumors, Bellicum chief executive officer Tom Farrell said.

The goal: To be able to control the patient’s response and to minimize side effects.

Ziopharm Oncology, working with biopharma behemoth Intrexon, has a similar plan in mind. It’s developing what Dr. Laurence Cooper, the company’s chief executive officer, describes as “remote-controlled T cells.”

The idea is that the CAR-T cells it infuses will only be “turned on” to fight against the cancer if the patient is also given a drug called veledimex. If a patient’s doing poorly in response to the therapy, doctors can stop giving him veledimex.

Where Bellicum uses the “suicide switch” to kill the T cells, Ziopharm — which is based in Boston — tries to mute them, but leave them alive, so they can be reactivated later if the patient is able to tolerate further treatment.

“It’s a shame to use the ‘suicide switch,’ because you’ve taken a really good medicine and eliminated that from the person’s body,” Cooper said.

Bringing CAR-T to the mainstream

To learn more about CAR-T, physicians say it has to be used more broadly.

“If we can get cellular therapy out of academic institutions, and out into mainstream medicine, we’ll have more understanding of its power,” said Goff, the National Cancer Institute surgeon.

But that’s tricky because of the side effects. Education is critical: When any company rolls out a new therapeutic, part of its duty is to teach physicians how to appropriately use the product. This is exceptionally important with CAR-T therapy, said Dr. David Chang, chief medical officer of Kite Pharma.

“I don’t want to sugarcoat the adverse events for CAR-T therapies,” Chang said.

However, he said, CAR-T is meant to be a one-time therapy: After an intense burst of treatment, patients ideally recover from their cancers and go on to lead relatively normal lives. This “really is moving away from the paradigm of repeat chronic treatment we’ve become accustomed to in oncology,” he said — so he thinks with training, it could someday become fairly routine in hospitals across the country.

“I don’t think this is a treatment that we foresee will be limited to comprehensive cancer centers or specialized hospitals,” Chang said.

Others aren’t so sure, at least not yet: “Whether this will be technology that’s specific to boutique, high-end academic centers, or technology that can be used in community hospitals if people learn how to infuse them in a safe manner — we just don’t know yet,” said Dr. Renier Brentjens, director of cellular therapeutics at Memorial Sloan Kettering, who is working with Juno on its CAR-T treatment. 

As for Koehler, these days she feels good — for the most part. Her energy levels are better than they were before the CAR-T therapy, and the cancer-free diagnosis has kept her spirits aloft. But she needs regular infusions of immunity-boosting drugs, because her new T cells are still killing off other immune cells. Koehler can’t work, and she still gets sick very easily.

Despite the agonizing side effects, she said she’d do it all again.

“When we realized I had a nuclear bomb in my body, we were very scared,” she said, “and when we learned that I was cancer-free, all I could think was, ‘How blessed am I?’”

Correction: An earlier version of this story misstated Dr. David Chang’s title and Juno’s assessment of the patient deaths in its clinical trial. The credit for the photo of Karen Koehler was also inaccurate.

  • As I know all cells in human (not only human!) body has its own and unique electrostatic charge. This is the way how ‘body knows’ what is ok and what is not ok. What body has to kill and what kind of cell body needs. Believe, that measuring this ‘electrostatic’ (mean cell + and – ions charge) marker is the key to precise kill what we want. For instance, if some (cancer) cell absorb all what have electrostatic marker A, why not to make similar chemical (same marker) with poison and put it near the cancer cells?

  • You have got to be kidding me! I would never allow my body to be treated with that crap. Why do we have to submit ourselves to the harmful, over priced experiments of pharmaceutical companies who are seeking their next billion dollar treatment or drug? Too many Americans are so afraid to die that they forget about how they are going to live as a result of some of these crazy treatments modern medicine has concocted, including chemo.

    In the event of a diagnosis of cancer for me, I would have to forgo all aspects of modern medicine, other than surgery to remove a large tumor or blockage and maybe some pain management. I would have to rely on my knowledge of natural medicine to do the rest and medical marijuana would be at the top of the list. I am not afraid of death, it’s the living part that’s scary, dealing with the insanity of modern medicine and what the industry will do to our bodies, to profit from our misery.

    • Avon, Hopefully you will never need a therapeutic treatment for cancer,.. but if you did…. I will advise you that the science behind the current treatments in the clinicals… is light years beyond what’s current SOC (Standard Order of Care)… The first thing newly diagnosed cancer patients need to do is to educate themselves about clinical trials… The SOC of radiation and chemotherapy is the equivalent of blunt force trauma to your body… and your life… Don’t trust it! The new(er) immuno therapies are showing significant promise to train your own immune system to identify the “non-self” cells and destroy them… In simple terms… it’s rocket science… I will refuse chemo and radiation in lieu of joining a trial that involves immunotherapy… there’s no comparison… Do your own due diligence… I have.. I choose life!!

    • Mark – But please keep in mind that these are trials for a reason. There is significant risk of a sooner death or worse outcomes while these things are being figured out. There are different risks either way, but please don’t minimize the risks of the trials.

    • To Avon (and others who replied): This is a wise attitude.
      Nick is right and Mark is wrong – or at least – naive.

      If chemo and radiation are crude, so is immunotherapy, except that the latter is unproven. Their underlying mechanistic rationale – merely a cartoon – is of course appealing and seducing. But immunotherapy is equally primitive in concept and it is a time bomb itself. It is not rocket science. It is based on the very crude, simplistic concept of being more precise and potent at killing. But the problem is in the very act killing itself. This is like moving from carpet bombing to smart-bombs launched from drones: The latter sounds high-tech and clean and powerful, and well, like rocket science, but will not win the global war on terror. The surviving terrorists will be angered and empowered by the killing of their comrades and adapt. They become fiercer and stronger an smarter. That is what we have now.

      What most of my cancer research colleagues do not know: Every time we kill a cancer cell, the dying cell sends signals to its neighboring non-killed cancer cells (which are almost inevitable). These signals switch them into the more aggressive stem-cell-like cancer cell, which are more resilient, versatile and can go into hiding: They are the seeds for recurrence. The cytokine storm is what causes this adaptive response (it is part of a misguided but evolved and deeply pre-wired regenerative response in the cells). This is why recurrent tumors are always so much more aggressive, immature, robust – just closer to stem cells.

      Thus, like in the war on terror the same applies to the war on cancer when we focus on more powerful kill-agents: “What does not kill me, strengthens me”… is the motto of the cancer cells, too.
      (see: )

      Of course in rare circumstances, the efficiency of killing of cancer cells outweighs this strengthening response because there are only few surviving cancer cell, much as in rare cases, bombs alone can win a war (but hardly a guerilla war). But this is rarely the case. Let’s hope that in the case of Karen Koehler this WAS the case – but I would not bet on it. Killing in fact is more efficient in non-solid cancers like CLL; so there is reason for hope.
      But in general: Nothing is more effective in generating cancer stem cells than the cytokine storm that the therapy, chemo, radio or immuno, elicits.

      But at least, the new therapy buys some time, perhaps a lot.

  • I have NHMCL. This is a form of lymphoma. I have been in remission for going on ten years. I had a stem cell transplant that actually put me in remission. Luckily I did have insurance otherwise I would have to pay close to $1m. The trial for the car-T sounds so promising. But again if you didn’t have insurance you would be out of luck or being part of a trial maybe you don’t need to have health insurance. That makes me sad to think about. Even if and when I relapse I may not be a candidate for this new therapy once it has been approved after its trial period. I am also sad that our government doesn’t have better control over pharmaceutical companies. It seem the pharmaceutical companies have the control over our government. Hopefully things will change in my left time. But the article is promising none the less.

    • I WISH I could get ablative chemotherapy/stem cells for my MS. My friend has been in remission from ovarian cancer going on ten years, she would be dead if she didn’t have the chemo. Your quality of life isn’t so hot when you have aberrant cells or cells behaving abnormally.

  • Yeah, good luck with this treatment in America. Insurance companies would rather have Americans die than pay that amount for saving a life. America is a screwed-up country. It’s slipped across all indicators of a “powerful” country. It’s ranks 37th in Standard of Living and unlike 42 countries that have Universal Health Care, America has none. You can thank the American Government for allowing Large Pharma and Health Care Insurance Companies the right to form unchallenged monopolies. In the meantime, the cost of medicines and health care continue to rise beyond the ability for most Americans (especially retirees) from accessing life-savings drugs. Perhaps the Government’s covert agenda of killing off the old, sick and infirmed will work as a means to limit Medicare payments moving forward. What a twisted Country of pathetic legislation.

  • I think it is wonderful-however- I live in a right to die with dignity state, and I will take that walk if I become terminally ill. I will not be a guinea pig for big pharma, they can keep you alive, at what cost? forget the $$$$$ the cost of your dignity, the cost of watching your loved ones watch you die, the constant sickness, the constant wondering, worry, the constant fear, the constant doctors visits.. no thanks, we all have to go sometime….

    • Before your “die with dignity”… simply do some research… Science is progressing by leaps and bounds…. What used to be a prognosis of 6 mos. is now being stretched out considerably… thanks to immunotherapy. Don’t take my word… do your own due-diligence! Peace!

    • I do not know what kind of “Dr.” you are, but you obviously are not aware of the great excitement in the myeloma (blood cancer of the bone marrow) community for Car T-cell therapy. Mitigating the cytokine storms is definitely a major challenge. Nonetheless, MSKCC for example will start trials for myeloma patients in 2017:

      “Memorial Sloan-Kettering is a global leader in CAR T cell technology and immunology, and, in the first half of 2017, we are excited to open our first CAR T study for patients with relapsed myeloma”, says Dr. Landgren, Chief of Myeloma Service at MSKCC. ”

      Why do you consider this a “pseudo scientific” treatment given that it is being pursued at one of the premiere cancer treatment centers in the U.S.?

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