The human immune system is both clever and powerful. But it is often foiled by cancer’s wily ways.
A new approach to cancer treatment — immunotherapy — aims to unmask the disease for the deadly threat it is, then direct the full force of the immune system on malignancies that would otherwise grow and spread unchecked.
Our multilayered immune defenses spot most foreign invaders and crush them decisively. But cancer, arising out of one or more mutations in our DNA, is a home-grown threat with a deceptively reassuring look. Even as cells multiply and spread, malignant cells cloak themselves in innocent garb.
Confused, the immune system pulls back its talons. And cancer has its way with us.
Immunotherapy can change this.
It stems from a growing understanding of how cancers start, grow and protect themselves from both medicines and our bodies’ natural defenses. It also capitalizes on researchers’ efforts to unpack the exquisite complexity of the immune system, including when and why it retreats from a fight.
The first generation of immunotherapy drugs is designed to release the “brakes” that inhibit the immune system from attacking cancers. By various means, they block an antibody that spares cancer cells from a sentence of “programmed death” issued by the immune system.
These so-called PD-1 blockers are the first of a class of immune checkpoint inhibitors. They are used to treat a wide range of advanced malignancies, including melanomas and cancers of the lung, breast, colon, bladder, thyroid and endometrium.
The first checkpoint inhibitor, a medication called Yervoy (ipilimumab), was approved for U.S. patients in 2011. The drug improved survival time for patients with metastatic melanoma from an average of six months to 10 months. Next came Opdivo (nivolumab) in 2014, which extended survival for patients with certain head and neck cancers, small-cell lung cancers, Hodgkin lymphoma, and some advanced colorectal cancers.
Half a dozen more immunotherapy drugs followed, including Keytruda (pembrolizumab) for lymphoma, metastatic head and neck cancers, non-small cell lung cancers and advanced melanoma.
These drugs tend to help more patients than standard therapy does, and with less punishing side effects. They extend average survival in large groups of patients — sometimes just by months, but generally by spans that are considered meaningful.
And for a small subset of patients whose prognosis is bleak, these drugs can drive cancer into outright remission. This is what instills the greatest hope in cancer doctors.
The approach doesn’t work for everybody. In rare cases, it sends the immune system into overdrive — a complication that can be uncomfortable at best and fatal at worst. This summer, the FDA halted a clinical trials in which Keytruda was being tested in conjunction with some other immune-boosting drugs to treat multiple myeloma, citing an increased risk of death.
The prices for these drugs is another drawback. Both Opdivo and Keytruda can cost $150,000 per year, a bill insurers are reluctant to pay and one that makes bioethicists concerned about unequal access.
Still, the drugs’ overall impact is clear, said Dr. Antoni Ribas, a melanoma specialist at UCLA who has conducted clinical trials on Keytruda. Immunotherapy drugs, he said, “are changing how we treat cancer.”
Just ask Kathy Thomas.
Five years ago, she was fighting a losing battle against metastatic melanoma that had spread to her breast, brain, lungs and liver. Her doctors feared she wouldn’t live to see the birth of her grandson.
Then she enrolled in one of Ribas’ clinical trials of Keytruda. Monthly infusions have made her cancer undetectable.
Last month, she celebrated her grandson’s fifth birthday.
“I would not be here if not for this drug,” said Thomas, 62.
Her experience is hardly unique. In an ongoing trial called Keystone, drug maker Merck & Co. reported this summer that close to 42% of subjects with metastatic melanoma who received Keytruda were still alive four years into the study. Some 13% of the subjects who received Keytruda had a “complete response,” and most had ceased taking the medication.
When Ribas started as an oncologist 18 years ago, “maybe one in 20 patients” lived for more than a year after being diagnosed with metastatic melanoma, he said. Now, thanks to immunotherapy drugs, “more than a third of my patients are living normal lives.”
Some cancers have proved more resistant to immunotherapy than others. Those that tend to afflict children or have weak ties to modifiable risk factors like smoking, obesity, poor diet and pollution can’t be stopped just by lifting the immune system’s brakes. To fight these cancers, the body seems to need a more specific assist.
Enter CAR-T cells.
For this approach, doctors start by harvesting a cancer patient’s T-cells, the warriors of the immune system. Scientists genetically engineer the cells to home in on the patient’s cancer and then grow millions of the modified cells in the lab. When the cells (now called chimeric antigen receptor cells, or CAR-T cells for short) are returned to the patient, they are much better equipped to hunt down and kill the cancer cells wherever they may hide.
So far, only one CAR-T immunotherapy treatment has been approved for use by the Food and Drug Administration — Kymriah, a drug designed to treat children and young adults with B-cell acute lymphoblastic leukemia who didn’t respond to standard treatment, or who suffered a relapse. Researchers tested it in 88 such patients ages 3 to 23, and it produced remission in 73 of them.
When FDA Commissioner Scott Gottlleib announced Kymriah’s approval in August, he predicted that many more CAR-T immunotherapies would follow. Dozens are currently in the pipeline, mainly aimed at treating cancers of the blood and lymph systems.
Dr. Crystal L. Mackall, a pediatric cancer specialist at Stanford, predicts that such “living drugs” will be “the beginning of a new era in medicine.” She calls them “the next frontier” in fighting cancer.
Pills and injections can target the processes by which cancers start and grow, said Mackall, who directs Stanford’s Parker Institute for Cancer Immunotherapy. But the effects of these treatments inevitably wane, and they must be renewed with another pill or injection.
“Cells can do things that drugs can’t do,” she said. “We’ve seen the dramatic effects of turning your cells into small machines, and this is just the beginning. They can be so much more sophisticated.”
“In many ways, we’re at the end of the beginning of immunotherapy: There’s clear benefit, but it’s still a minority of patients that get long-term benefit,” Markovic said. “We will get better at this.”
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