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.
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.
Wouldn't it be great if your immune system could snuff out cancer as easily as it conquers the common cold?CLICK TO TWEET
“For decades, the backbone of cancer treatment has been surgery, radiation, and chemotherapy. Then we moved to an era of targeted medicine,” explains Dr. Robert Figlin, deputy director of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. “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.
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.
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.”
“There’s no doubt in my mind that immunotherapy will eventually be a standard in almost every cancer.”
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.
Not everyone responds to checkpoint inhibitors. In fact, most patients don’t respond at all.
Melanoma patients have had the most success. 30-40% of patients respond when taking just one checkpoint inhibitor; that number nears 60% 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% 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 20-40% of patients responding. In other cancers, like breast and ovarian, response rates are a dismal 10%—the treatment doesn’t work for 90% of patients.
The question: Why?
“We don’t fully know,” says Dr. Omid Hamid, chief of Clinical Research and Immuno-Oncology and director of the Melanoma Program at The Angeles Clinic. “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.”
Not everyone responds to checkpoint inhibitors. In fact, most patients don’t respond at all.
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,” Dr. 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.
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 Dr. Jethro Hu, a neuro-oncologist at Cedars-Sinai and an investigator for a Phase II clinical trial studying checkpoint inhibitors in glioblastoma, an aggressive brain tumor.
That over-amping 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.
“The toxicity profile for some checkpoint inhibitors is modest, but there can be infrequent, life-threatening adverse events,” Dr. Figlin says. “Usually, we can manage those risks. But it’s not like taking a blood pressure pill.”
“We have to find out what makes the patients who do respond special. 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.”
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 Dr. Ronald Natale, 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.
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.
Experts don’t envision immunotherapy as a substitute for traditional therapies like surgery, radiation, and chemotherapy—at least not in most cases.
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,” Dr. 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,” Dr. 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.”
This post is an abridged version of “The Weapon Inside” from Discoveries magazine, which covers medical research at Cedars-Sinai and its impact on patient care. To learn more about immunotherapy research and see how it’s working for one melanoma patient, read the full story.
