Enrolling the immune system in the fight against cancer

THAT infections could sometimes cause a cancer to retreat, or even vanish, was known well before the advent of modern medicine. Imhotep, a pharaoh, recommended treating a tumour with a poultice followed by an incision—something that would help an infection develop. In early modern Europe doctors used septic dressings on tumours with ulcers and deliberately created purulent sores. By the end of the 19th century, William Coley, a bone surgeon in New York, was methodically infecting patients with Streptococcus bacteria.

Coley’s work fell out of favour, partly thanks to the rise of radiation therapy. Many continued to cling to the idea that the immune system might in some circumstances be provoked into recognising, attacking and subduing a cancer; they just didn’t know how to provide the provocation. In 1976 this latent belief in the potential of “immunotherapy” blossomed into hope with the discovery of interleukin 2 (IL-2). IL-2 is a growth factor that encourages the production of T-cells, white blood cells that scan the body for unwanted invaders and, on finding them, activate other parts of the immune system, including the B-cells which produce antibodies.

But IL-2 was a false dawn. On its own, it activated the immune system indiscriminately, and the immune system is a powerful beast; Elad Sharon, at the National Cancer Institute’s division of treatment and diagnosis, says the effects were “toxic and messy, and frequently sent patients to the ICU.” That might have been more tolerable in a drug that delivered. But to general surprise and discouragement IL-2 cured only a few patients of metastatic cancers. It was not clear why the treatment was not more effective.

Answers started to arrive in the 1990s. James Allison, at the Cancer Research Laboratory at the University of California, Berkeley, began work on a protein called CTLA-4 on the surface of some T-cells. By 1996 he had shown that this protein put a brake on the immune response to cancer. Blocking CTLA-4 with an antibody removed the brake; the immune system activated itself and got to work. Tumours in mice vanished when the animals were given CTLA-4-blocking antibodies. Though it was not immediately obvious, in retrospect this came to be seen as one of the reasons IL-2 never really worked: it is not possible to make a car run faster if its brakes are jammed on.

At the time oncologists were unimpressed by Dr Allison’s results. Cancer had been cured in mice many times over. And after many failed trials, immunotherapy was in exile—banished to the small corners of the big oncology meetings. But in 1999 Tasuku Honjo of the University of Kyoto, in Japan, showed that the gene for a protein called PD-1 also seemed to tamp down the immune system. When this gene was switched off in mice, some developed autoimmune diseases—a sign of an immune system in overdrive. In collaboration with Arlene Sharpe and Gordon Freeman at Harvard, Dr Honjo showed that some cancer cells had a second protein called PD-L1 on their surfaces which, by interacting with the PD-1 on T-cells, protected the cancer from them. Dr Honjo remembers approaching many companies with the finding, but “none wanted to invest.”

Despite a general wariness on the part of pharma companies, though, a trickle of development on therapies aimed at CTLA-4 and PD-1 did begin. Then, in 2010, Bristol-Myers Squibb released results from a trial of an anti-CTLA-4 antibody, Yervoy (ipilimumab), in malignant melanoma. Compared with the state of the art, they were fantastic. It was the first drug shown to change survival in this devastating disease, raising the median to ten months. Some survived much longer.

What was going on? Because the immune system is such a powerful beast, evolution has equipped it with a system of checks and balances lest it get out of hand. Both CTLA-4 and PD-1 are parts of that system. When one sort of immune cell presents an antigen which it has picked up to another, the second cell will ignore it if, at the same time, the first cell stimulates the CTLA-4 receptor. If the CTLA-4 receptor is blocked with an antibody like Yervoy, though, this “checkpoint” system does not work. Unchecked, the immune system is able to react to a wider range of antigens—including tumour antigens. Freed up by Yervoy the body’s T-cells started attacking the melanomas. And, it turned out, kept on attacking them. Perhaps the most remarkable feature of the new “checkpoint inhibitor” was that a small subset of patients survived for year after year.

Despite indications of success with melanomas, many scientists thought the checkpoint-inhibitor mechanism would not be broadly effective. Melanomas accumulate a very large array of mutations, and are thus more likely than most cancers to display antigens which trigger an immune response. This argument was bolstered by the observation that melanomas are more likely than other cancers to be subject to spontaneous remissions—presumably because something else kicks the immune system into gear. What was more, Yervoy had serious, sometimes life-threatening side-effects.

Pessimists have a pretty good record when it comes to cancer prognostication. But this time they were wrong. At Merck Roger Perlmutter, an immunologist who had previously left the company, was brought back to run the research labs. He became very interested in a PD-1-blocker then known only as MK-3475. Unlike CTLA-4, which works higher up the immune system’s chain of command, PD-1 has a front-line role; if a cancer cell carries PD-1’s counterpart, PD-L1, on its surface, T-cells will ignore the cell despite any suspicious antigens it may be carrying (see diagram). MK-3475 seemed to block the interaction nicely. It might thus render the immune system blind to the cancer’s subterfuge. “Whatever [else] you are doing, stop,” Perlmutter told his clinical-development group. Merck expanded a phase 1 trial programme looking at the drug’s effect on advanced melanoma to more than 1,200 patients, making it the largest phase 1 trial in the history of oncology.

The expansion was in part a response to a new discovery: early evidence suggested that checkpoint inhibitors could also get results with lung cancers, which are a much bigger killer than, and thus represent a much larger market than, malignant melanomas. Luis Diaz, head of solid-tumour oncology at the Memorial Sloan Kettering Cancer Centre in New York, recalls: “It was completely unexpected. Prior to that I was not a believer in immunotherapy.”

Whispers of a cure

Merck’s PD-1 drug would eventually be given the commercial name Keytruda (pembrolizumab). In 2014 it became the second checkpoint inhibitor to be approved in America—the world’s largest and most lucrative pharmaceutical market. Opdivo (nivolumab), a PD-1 drug which Ono Pharmaceuticals had developed on the basis of Dr Honjo’s work, soon joined it, having been licensed in Japan a little earlier. In some cases the drug produced effects little short of miraculous. In 2016 it was announced that it had cleared former president Jimmy Carter of metastatic melanoma that had spread to his liver and brain.

In lung cancer, and in many other cancers, the patients who responded tended to have a higher mutational burden, like that seen in melanoma. More antigens means more targets for the immune system to tackle when the drug lets it off the leash. This observation provided a way to spot some of the patients most likely to benefit. In 2017 Keytruda was approved for use in any cancer that has mismatch-repair-gene defects, a flaw which means that a cancer accumulates even more mutations—and thus more possible antigens—than most.

Another indicator that the drug may have something to offer is the tumours’ expression of PD-L1. Tumours expressing a lot of PD-L1 are investing in keeping the immune system duped; when the PD-1 system is interrupted they should prove particularly vulnerable. At the start of October 2015, Keytruda was approved for use in advanced non-small-cell lung cancer in cases where other treatments had failed and when there was PD-L1 on more than 50% of the tumour cells. Ms Milley’s score was 80%, and she started treatment almost immediately.

Jedd Wolchok, a medical oncologist at Memorial Sloan Kettering, says immunotherapies do not have the same kinds of impact as other types of cancer therapy. In some cases they do not work at all. In other cases they can either eliminate the cancer entirely, or cause it to stabilise, or regress. Responses to therapy are often longer lasting than those seen in targeted drugs. And they tend to persist after patients stop taking the drug (at present CTLA-4 drugs are usually administered for only a matter of months).

The nature of the long-lasting responses is intriguing. Dr Wolchok has patients who started treatment for malignant melanoma eight years ago. He finds it particularly interesting that in some cases scans of the cancers taken before treatment (when the prognosis for the patients would have been six or seven months) and scans taken today look more or less equally dreadful. Biopsies of the tumours reveal a lot of immune cells and a lot of dead tumour cells. Dr Wolchok says it looks like a “chronic struggle between a patient’s immune system and cancer”. This apparent equilibrium is quite different from what is seen in chemotherapy, where the cancer will be either susceptible or resistant. The difference seems to be due at least in part to the fact that the immune response, like the cancer, can evolve.

Though immunotherapy is still new, it has already radically shifted the treatment and research landscape. A wide range of combinations is being tested in the hope of improving patients’ responses. A trial combining Opdivo and Yervoy in malignant melanoma has shown tumours to shrink in 60% to 70% of patients (although it causes serious side-effects). Dr Wolchok says it is not yet possible to calculate the median survival time in the trial population—because more than half of the patients are still alive.

Compared with the more limited range of patients that can be treated with most targeted therapies, immunotherapies seem to work in many cancers. And as Dr Sharon at the NCI points out, it also produces cures. But this excitement needs to be tempered with the grittier reality that, across all cancers tried so far, only about 20% respond to the new approach. The response varies greatly between types of cancer. In patients who have failed the usual treatments for Hodgkin’s lymphoma it is 90%. In pancreatic and most colorectal cancers it is basically zero.

Improving this response is perhaps today’s biggest oncological challenge—the source of more excitement, and investment, than any other recent development in the field. Part of the answer will come from a better understanding of the steps needed to generate an anti-tumour response from the immune system, and of the therapeutic targets available. For example, Hervé Hoppenot, the boss of biotech firm Incyte, a biotech firm based in Wilmington, Delaware, says that some tumours protect themselves from the immune system using another checkpoint, IDO1 (an enzyme that was first discovered in a search for ways to protect a fetus from immune rejection). Incyte is testing epacadostat, an existing drug known to inhibit IDO1, as a cancer treatment both alone and in combination with PD-1 blockers.

There are well over 1,000 clinical trials of checkpoint inhibitors going on; what was at first a trickle, then a current, is now a torrent. Some worry that things have gone too far too fast. Jeff Bluestone, who runs the new Parker Institute for Cancer Immunotherapy in San Francisco, says “many of [these trials] are based on minimal data and very limited clinical evidence about what combination will work”. Some fear there are too few patients to allow these trials to be run, others that there is too little thought and planning and a lot of duplication of effort. Dr Freeman at Harvard says he has been told there are over 80 Chinese groups developing different PD-1 antibodies.

This enthusiasm may lead to wasted efforts, and even delay progress. But there is no doubt that immunotherapy will from here on be a key part of treatment for a growing number of cancers. Perhaps the most telling measure of its success is that some oncologists have started to complain, quietly, of a shortage of specialist doctors. Patients keep coming back instead of dying.