For the last couple of years, we have been bombarded by news of the amazing response rates of cancer immunotherapies in patients who had lost all hope, intermingled with success stories of patients surviving against all odds. There is no doubt that new immunotherapy treatments are gaining ground on the cancer battlefield, but we might have to remind ourselves that the battle is not yet won — patients do relapse.
This fact was grippingly illustrated in Matt Richtel’s story of his friend fighting Hodgkin’s lymphoma, recently published by The New York Times. Jason Greenstein, featured in the story, had been trying to fight off his lymphoma for four years with various chemotherapy drugs, and, as with many others, was offered an experimental immunotherapy treatment as a last resort.
Cancer immunotherapy uses an entirely new concept in trying to beat cancer, compared to older methods. These treatments, such as chemo and radiotherapy, made use of the fact that cancer cells divide rapidly. By using drugs that kill dividing cells, a tumor can be conquered. Their drawback, of course, is that the body holds millions of other rapidly dividing cells that get killed in the process, giving rise to the numerous side effects of chemo — stomach problems, hair loss, and a wipeout of immune cells — often taking a worse toll on the health of a patient than the tumor itself. At least in early stages of disease.
Greenstein’s oncologist, Dr. Mark Brunvand. expressed his view of chemotherapy in the NYT article, saying, “When you have cancer, you spread napalm on it and burn everything to the ground.”
The immune system is a complex machine. Despite what people used to believe, it really has the capacity to fight cancer. The problem is — researchers realized some time ago — that tumors can actually control when the immune system turns on. And, when the immune system unleashes its unrestricted wrath, it has the capacity to kill more than just bugs and tumors, it can actually kill us, too.
Evolution has invented numerous ways to keep the immune system quiet unless needed, and to allow immune cells to see a difference between a cell belonging to the body and intruders or cells that don’t look or behave as normal cells, such as tumors. But as most mechanisms in our body aiming to protect us, they can fail.
In autoimmune diseases such as rheumatoid arthritis or scleroderma, immune cells start attacking the organs of its host. The opposite is seen when a tumor evolves. Cancer cells are awfully good at making the immune system’s safety checks work in their favor, hijacking the brake molecules to make sure the immune system treats the tumor just like any other cell — and leaves it alone, or rather kills itself.
Two of the most well-studied molecules in this system, PD-1 and PD-L1, virtually activate a self-destruction program in all T-cells they encounter. PD actually stands for programmed cell death.
Immune checkpoint therapy — the type of treatment Greenstein received — blocks these molecules, often found in large numbers on cancer cells. This allows the immune system to ‘see’ the cancer for what it is, attacking it as feverously as if it was a microbe invading the body.
Greenstein’s immune treatment was nivolumab, or Opdivo as is it called by its brand name, a checkpoint inhibitor that was first approved for advanced melanoma in December 2014. One month later, a group of researchers from cancer centers across the U.S. published a report describing the effects of Opdivo in 23 patients with Hodgkin’s lymphoma.
Richtel’s story of Greenstein, his childhood friend, tells that by the time Greenstein got his death sentence, Opdivo had not been approved for Hodgkin’s yet, and with evidence from only 23 patients, Greenstein’s oncologist knew that trying the drug was a shot in the dark. And yet, shots in the dark can often save cancer patient’s lives.
After four years of failed treatments, with tumors the size of melons protruding from his body, Greenstein responded miraculously well to the drug. A series of pictures taken by Greenstein’s girlfriend illustrated that the bulging body of a near-death cancer patient was transformed to that of a normal, slender man in only six weeks.
“I watched the moon landing in 1969, and it was a similar sense of awe,” Dr. Brunvand told the Times. But although these are the stories we usually hear, an initial response seemingly cheating death, the fact is that even immunotherapy can’t cure all.
It turned out that Greenstein’s case fell among the less cheerful statistics. The story tells us how, despite the initial response, Greenstein relapsed less than six months later. New courses of radiotherapy followed. Again, he seemed to have beat the cancer, making plans of new business initiatives instead of slouching through cancer treatment rounds.
And again, he relapsed. With Hodgkin’s being a cancer type cured in about 90 percent of patients, Greenstein is, for sure, exceptionally unlucky, having a cancer that might turn out to be more stubborn than himself. Reading the story, it is easy to lose track of how many times Greenstein relapsed, and yet came back each time with an exuberant will to live, earning him the nickname ‘steel bull’ from his oncologist.
About a year after his first immunotherapy treatment, another relapse pulled the rug from under his feet. New tumors in his spine, along with years of bone-depleting drugs, made his spine collapse. New rounds of immunotherapy followed, and as surprisingly as the first time, the tumors quickly disappeared. Within a few weeks of his last treatment, scans showed no traces of cancer in his body. But with a broken back, the possibility of leaving the hospital seemed far off.
Richtel’s story of his friend is a heartbreaking tale of one person’s fight, but Greenstein is not alone. Behind the success statistics, with some studies reporting 80–90 percent remission rates, are other failures. The 10, 20, or 30 percent of patients not responding well enough to treatment. Or the relapse patients, not receiving as much media coverage when they relapse as when they walk away smiling from the cancer ward. In fact, studies show that long-term survival for patients treated with checkpoint inhibitors is reserved for a lucky few.
“We’re in the honeymoon period,” Dr. John Timmerman, one of the oncologists behind the Nivolumab Hodgkin’s early study, told Richtel. “Patients are responding. They are also relapsing.”
At the moment, doctors don’t know why some patients respond fabulously well to immunotherapy, while others don’t. Or, like in Greenstein’s case, the tumors come back. Some answers might be sought in the genes of a tumor, and researchers are building huge libraries of tumor genomes that might aid in the identification of proper treatment. A tumor might be located in the gut, but if its genes are more similar to a kidney cancer, maybe a kidney cancer treatment will work?
And scientists also believe that our gut microbes, through their impact on the immune system, can impact how a patient responds to cancer immunotherapy.
Combining different types of immunotherapy might improve the odds for patients such as Greenstein. CAR T-cell therapy — a treatment that remains in the experimental stage — takes a patient’s own T-cells and modifies them to a more aggressive immune cell in the laboratory before they are allowed back into patients to fight a cancer. Researchers now experiment with combining CAR T-cells with checkpoint blockers, and other immunotherapy options also exist.
Yet, for patients like Greenstein, going through relapse after relapse, such efforts might come too late. A few weeks after scans showed that the cancer, once more, had left Greenstein’s body he slid into an unconscious state. His oncologist could not find any clues of what could be causing the condition, suggesting encephalopathy, or temporary brain dysfunction. The treatment seemed to have got the better of him, with inflammation rummaging his brain.
But as the jack-in-the-box of his own story, he greeted Independence Day by once more coming back to life.