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discoveries magazine

The Weapon Inside

Kathy Dailey’s body is a weapon against melanoma. Turning our immune system against tumor cells seems like an elegantly simple strategy to defeat cancer. After years of failure, immunotherapy is finally working wonders for some cancers, transforming death sentences into long-term remission. But it doesn’t work in most cancers — at least not yet.

Kathy Dailey

Photo: Max Gerber

The worst news of Kathy Dailey’s life came, fittingly enough, on Friday the 13th. That’s the day she learned that her melanoma — surgically removed two years before when it was at an early stage — had returned with a vengeance, metastasizing to her liver and lungs. Her oncologist recommended chemotherapy and said she had a year or two to live.

At 55, the Southern California resident was in a sweet spot in her life. She loved her job in media, was active and fit, had a passion for exercise, and often spent weekends taking long hikes with her boyfriend, Ron Ripperger.

Now, all she could think was, “I’m not going to live to be 60.” A few days later, she sought a second opinion at The Angeles Clinic & Research Institute (an affiliate of Cedars-Sinai). In the exam room, she told the nurse practitioner taking her blood pressure about her prognosis. To her surprise, the nurse scoffed.

“Oh, that’s so 2012,” she told Kathy, dismissing the bleak scenario with a wave of her hand, as if she were batting away a fly.

It was September 2013. And the nurse was right. There was hope, and it came in the form of a new, cutting-edge cancer treatment, one that Kathy had never even heard of: immunotherapy.

Wouldn’t it be great if your immune system could snuff out cancer as easily as it conquers the common cold? Scientists have been dreaming about that possibility for more than 100 years, but, today, the idea of harnessing the immune system to fight cancer is no longer a pipe dream. It’s real — and it’s big.

Patients have watched astounded as incurable cancers seemingly vanish into thin air. The most famous such patient: former President Jimmy Carter, whose advanced melanoma, an aggressive skin cancer, disappeared in 2015 after treatment with surgery, radiation, and immunotherapy. Most exciting of all, immunotherapy-induced remission can be long-lasting, sometimes extending to 10 years or more in patients who once faced death sentences.

Illustration: Edmon de Haro

“For decades, the backbone of cancer treatment has been surgery, radiation, and chemotherapy. Then we moved to an era of targeted medicine,” explains Robert Figlin, MD, deputy director of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and the Steven Spielberg Family Chair in Hematology-Oncology. “Now, we are entering the era of immunotherapy.”

While today’s immunotherapy takes many forms, the most talked-about breakthrough is a class of drugs called checkpoint inhibitors. The drugs have made their biggest splash with melanoma but now are approved for such cancers as kidney, lung, bladder, and head and neck. They’re being studied in dozens more malignancies, and pharmaceutical companies have been filling their pipelines to capacity with new compounds. Clinical trials abound.

Could this be the long-hoped-for cure for cancer? Possibly — for some patients. But immunotherapy has a sobering side, too. First, revving up the immune system comes with the very real risk that it will go into overdrive, attacking healthy organs. Second — and perhaps most troublesome — immunotherapy doesn’t work for everyone.

Actually, it doesn’t work for most patients.

Now, scientists are on a mission to find out why, while also expanding immunotherapy to more patients and more cancers — without making it too toxic in the process. Along the way, they’re slowly cracking the code to one of cancer’s oldest and most closely guarded secrets: how it evades the one enemy that could easily destroy it.

On Oct. 17, 2013, Kathy found herself sitting in a tiny, cold infusion room, a blanket wrapped around her, Ron at her side, and an IV solution drip-drip-dripping into her left arm.

It was her first immunotherapy infusion, part of a clinical trial suggested by her new doctor, Omid Hamid, MD, chief of Clinical Research & Immuno-Oncology and director of the Melanoma Program at The Angeles Clinic. Because the trial was double-blind, neither Kathy nor Hamid knew which of two substances — or a combination of both — was now slipping into her veins. But all the therapies were immunotherapy’s superstars: checkpoint inhibitors.

“Checkpoints” are proteins in our bodies that normally protect healthy cells from immune system attack by attaching to special receptors on T cells (powerful immune cells). The receptors act like “brakes” or “off switches,” and by activating them the proteins tell the T cells, “Stop! Don’t attack; this is healthy tissue.”

It’s an effective system. But cancer plays a sneaky trick: It uses those same proteins to masquerade as healthy tissue and tell approaching T cells to hit the brakes and turn off. This keeps cancer safe from immune system attack.

Enter checkpoint inhibitors. The drugs block certain checkpoint proteins so cancer can’t use them to disarm T cells. As a result, T cells now have free rein to attack and kill tumor cells.

Since 2011, four checkpoint inhibitors have been approved by the Food and Drug Administration: ipilimumab, nivolumab, pembrolizumab, and atezolizumab.

Kathy’s trial was comparing three protocols: ipilimumab, nivolumab, or a combination of the two. Both she and Hamid now suspect that she received the combination.

“She had a lot of side effects, and early side effects,” Hamid says. “That’s indicative of being on a combination.”

Not everyone responds to checkpoint inhibitors the way Kathy did. In fact, most patients don’t respond at all.

Even before that first infusion was finished, a metallic taste had arisen in Kathy’s mouth. When she and Ron arrived back at their apartment, she went into the worst chills of her life, followed by extreme hot flashes and digestive upset.

She lost her appetite; she lost weight. By December, after just a handful of infusions, her hair fell out in clumps — a side effect only rarely seen with immunotherapy. She developed various itchy rashes and agonizing muscle spasms.

“My body was going crazy,” she says.

But the treatment was working. By the end of December, her tumors had shrunk 36 percent. It was excellent news, but a week later, a blood test revealed that her liver enzymes were significantly elevated. She had to stop the infusions and begin a two-month course of steroids to calm her liver inflammation, a side effect of the therapy.

The astonishing thing is what came next. After six weeks, even without additional infusions, her tumors had shrunk to 50 percent.

It is one of the most exciting aspects of immunotherapy: “Once ‘trained,’ an immune system can sometimes keep killing the cancer, even without new infusions,” Hamid notes. In fact, Kathy’s cancer kept shrinking; she never resumed treatment.

Today, no active cancer is in her body. In the three years since her last infusion, she’s become a grandmother — twice — and she and Ron, together for 16 years, are talking about a wedding.

“I’m a walking miracle,” she says. “Every day is gravy.”

Not everyone responds to checkpoint inhibitors the way Kathy did. In fact, most patients don’t respond at all.

Melanoma patients have had the most success. Thirty to 40 percent of patients respond when taking just one checkpoint inhibitor; that number nears 60 percent when taking two drugs. That’s remarkable success for a disease that previously was a near-certain death sentence in advanced cases. But still, only about 34 percent of melanoma patients on checkpoint inhibitors survive five years or more.

So far, other cancers haven’t been able to match melanoma’s response rates. Kidney, bladder, and non-small-cell lung cancer have the next best results, with about 20 to 40 percent of patients responding. In other cancers, like breast and ovarian, response rates are a dismal 10 percent — the treatment doesn’t work for 90 percent of patients.

The question is: Why?

“We don’t fully know,” Hamid says. “Those cancers might not be as immune-stimulated, and they may have more immune-suppressive factors. So far, we’re not seeing the long-term durable responses with the majority of cancers that we’re seeing with melanoma. We have to do better. But we’ll get there. We’re slowly unlocking it.”

Illustration: Edmon de Haro

One major effort underway is to find more precise biomarkers — substances or molecules in the body that could predict which patients will benefit from which immunotherapy drugs. Finding better biomarkers is especially important because immunotherapy comes with risks and a high price tag — $3,000 or more per infusion.

Biomarkers also could help scientists better understand why certain patients respond so well — and help them re-create those conditions in patients who don’t.

“We have to find out what makes the patients who do respond special,” Hamid says. “It’s not man or woman. It’s not young or old. It’s likely something in their genome or their mutational status or their tumor microenvironment. That’s our focus.”

Researchers also are working to boost patient response rates. One strategy, which is already having success, is to borrow a page from chemotherapy’s playbook: Combine two or more drugs. Giving two checkpoint inhibitors releases more brakes on T cells, increasing the odds they’ll go after the cancer.

Of course, it also increases risk. And while newer combinations are showing signs of being less toxic, tactics to get more cancers and more patients to benefit from immunotherapy make more side effects seem inevitable.

“The big question is: Is there going to be that sweet spot where you can dial up the immune response enough to get the response you want without tipping into excess toxicity?” says Jethro Hu, MD, a neuro-oncologist at Cedars-Sinai and an investigator for a Phase II clinical trial studying checkpoint inhibitors in glioblastoma, an aggressive brain tumor.

Marilyn Michelson, 73, initially had only very mild side effects from her immunotherapy treatment. Marilyn, who has stage 4 lung cancer, began taking the checkpoint inhibitor nivolumab last summer. Prior to that, her tumors had shrunk 70 percent with chemotherapy, only to return quickly.

After just four immunotherapy infusions, Marilyn’s tumors were 90 percent gone.

“The day after an infusion, I’m a little tired,” she says. “And I sometimes get a touch of nausea. But it’s nothing compared to chemo. I thought chemo was going to kill me.”

But like Kathy, who had a hepatitis-like reaction to her immunotherapy, Marilyn’s immune system also soon went into overdrive, and she developed colitis (inflammation of the bowel).

Illustration: Edmon de Haro

That overamping of the immune system is the Achilles’ heel of checkpoint inhibitors. After all, those brakes on T cells are there for good reason. Release them too much and the T cells start attacking healthy organs, including the gut, liver, lungs, and pancreas. An article published last fall in The New England Journal of Medicine highlighted a new concern: heart problems. The study cited rare, scattered cases in which patients died after their immune systems attacked their own hearts, rejecting them as if they were transplants.

The key to preventing problems from escalating out of control is to catch warning signs early and put treatment on hold while calming the immune response, usually with steroids. That’s how Kathy handled her liver reaction. Marilyn, meanwhile, resumed immunotherapy after just a week on steroids.

“The toxicity profile for some checkpoint inhibitors is modest, but there can be infrequent, life-threatening adverse events,” Figlin says. “Usually, we can manage those risks. But it’s not like taking a blood pressure pill.”

When researchers examine tumor tissue from patients who have not responded to immunotherapy, they sometimes see astonishing scenes.

In some patients, they find T cells lined up, completely encircling the tumor but unable to get inside, blocked by some kind of chemical “moat.” Other times, T cells are inside the tumor but not attacking. They’re just sitting there, stupefied, like victims of a “stunning spell” straight out of Harry Potter.

“For a number of patients, activating T cells is not enough,” says Ronald Natale, MD, director of the Lung Cancer Clinical Research Program at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. “There’s something inhibiting their trafficking to the tumor and penetrating into it and actually killing the cancer cells.”

Investigators now are studying several novel molecules designed to direct T cells into a tumor and boost their ability to attack the cancer.

Experts don’t envision immunotherapy as a substitute for traditional therapies — at least not in most cases.

In fact, one of the problems with checkpoint inhibitors is that releasing the brakes on T cells only works if the T cells already are trying to mount an assault. It’s like a car: There’s no point hitting the brake and gas pedals unless the engine is running.

That’s likely why checkpoint inhibitors tend to be more successful against so-called “hot” tumors — tumors that have lots of T cells already roaming the area, snooping around, suspicious. Those T cells aren’t killing the tumor, but they’re there and, if you take their brakes off, they’ve got a fighting chance at knocking out the cancer, or at least landing a few well-placed punches.

Other tumors are “cold,” attracting few, if any, T cells. How do you make a cold tumor hot? The key is to stimulate an immune response. Scientists are now actively testing multiple ways to do this. One strategy? Turn up the heat — literally — with radiation.

“Radiation kills off tumor cells, and when those cells die, they release all of their contents, all these antigens,” Hu says. “That’s the window when we might have the most opportunity to mount an immune response.”

Indeed, most experts don’t envision immunotherapy as a substitute for traditional therapies like surgery, radiation, and chemotherapy — at least not in most cases.

“There’s no doubt in my mind that immunotherapy will eventually be a standard in almost every cancer,” Hamid says. “But I don’t see it as a replacement for things like chemotherapy. I see it as becoming another tenet of cancer therapy. It’s going to be its own discipline.”

Five years ago, Hamid would have 50 people show up in his office, clamoring to get into a clinical trial with only five available slots. Today, with so many immunotherapy trials, in so many different cancers, “we have many trials seeking subjects,” he says. “It’s completely changed.”

Those trials, ongoing at multiple Cedars-Sinai locations, including the Samuel Oschin Comprehensive Cancer Institute and The Angeles Clinic, are studying an array of immunotherapy compounds, targeting everything from new checkpoint proteins to immune-suppressing factors in the “microenvironment” around a tumor.

Immunotherapy is even being studied in earlier-stage cancers. One of the first such trials in this area — a Phase II trial testing pembrolizumab in localized bladder cancer — is taking place at Cedars-Sinai.

“If we give a checkpoint inhibitor to these patients, will it prevent the recurrence of their cancer down the road, so they don’t end up needing their bladder removed?” asks Timothy Daskivich, MD, a urologic-oncologist at Cedars-Sinai and principal investigator for the study. “That would be a huge advance.”

As these new studies continue, immunotherapy is fast becoming “another wheel on the cart of cancer therapeutics,” Figlin notes. Still, cancer is — and will continue to be — a very complicated and fierce opponent.

“Immunotherapy offers great opportunity to produce durable remissions and even cures in many patients,” Figlin says. “But we’re just at the beginning of the story.”

Beyond Checkpoints

Checkpoint inhibitors are just one way medicine is working to rally the immune system to fight cancer and win. Here are two other promising approaches:

Adoptive T cell therapy. This intensive therapy mostly has been used in blood cancers, including lymphoma. Patients’ T cells are collected from their own blood and genetically engineered in a lab to produce billions of proteins, called CARs, on their surface that recognize specific antigens on tumor cells.

When the T cells are infused back into the patient, the CARs help T cells find and kill the tumor cells. Results in preliminary trials have been promising. Researchers at The Angeles Clinic will soon be starting an early-phase clinical trial designed to show whether the treatment can be commercially viable.

Vaccines. Since the early 1990s, Cedars-Sinai has been researching a dendritic cell vaccine to treat an aggressive brain tumor called glioblastoma. As in adoptive T cell therapy, dendritic cells (a type of white blood cell) are collected from patients’ blood and then engineered in the lab so they can recognize certain components of glioblastoma tumors. The cells then are reinfused back into patients.

In a Phase I trial, median survival for newly diagnosed patients was 38 months — more than double the current life expectancy for patients. Phase II did not show the same survival benefit, but Cedars-Sinai is conducting a Phase III trial to evaluate the therapy in a larger number of patients.