美国研发的治肿瘤新药

Promising New Cancer Drugs Empower the Body’s Own DefenseSystem

By ANDREWPOLLACK

CHICAGO — The early success ofa new class of cancer drugs,revealed in test results released here over the last several days,has raised hope among the world’s top cancer specialists that theymay be on the verge of an important milestone in the fight againstthe disease.

The excitement has spread toWall Street. Shares of Merck and Bristol-Myers Squibb, which aredeveloping such drugs, rose more than 3 percent on Monday afterdata from their studies was presented over the weekend at themeeting of the American Society of Clinical Oncology.

Thedrugs, still generally in early testing, work in an entirely newway, by unleashing the immune system to attack cancer cells much asit attacks bacteria. That could be an alternative tooften-debilitating chemotherapy.

Finding ways to use the body’sown defenses has been a goal since the late 1800s, when a New Yorksurgeon named William B. Coley noticed thatcancer disappeared in a patient who had a severe bacterialinfection.

He then began injectingbacteria into cancer patients to rev up their immune systems. Hisclaims of success were disputed and most attempts since then toharness the immune system have not worked.

The new drugs work by disablinga brake on the immune system called the programmed death 1receptor, or PD-1. And although the data presented at the meetingwas from the earliest stage of testing only, the drugs were thecenter of attention here, with some doctors predicting that cancertreatment was about to shift.

“If you look five years out,most of this meeting will be about immunotherapy,” said Dr. MarioSznol, a professor of medical oncology at Yale.

Analysts, who predict billionsof dollars in sales, are trying to determine which of the threefront-runners — Merck, Bristol-Myers and Roche — have the best drugand how soon the drugs could reach the market. Some think it could be as early as a year and a half fromnow.

“I think all of you recognizethis is a very special moment in oncology,” Dr. Roger M.Perlmutter, head of research and development at Merck, toldanalysts Sunday at a standing-room-only meeting.

Harnessing the immune system isappealing for several reasons. It might be applicable to manydifferent types of cancer. It might produce longer lastingremissions than can be achieved by chemotherapy or the newertargeted drugs. And it seems somehow more natural andholistic.

“It seems the right thing to doto stimulate our body’s defense rather than take some kind ofpoison,” said Therese Bocklage, a cancer patient and pathologistfrom Albuquerque.

Dr. Bocklage thought she hadbruised her leg moving a Christmas tree in late 2011. It turned outto be the return of the melanoma shethought had been successfully eradicated by surgery 20 yearsearlier.

She has been taking Merck’sexperimental PD-1 inhibitor, lambrolizumab, as part of a clinicaltrial since January 2012, and her tumors have disappeared. “If Ihad had this turn up not last year but six years ago, most likelyI’d be dead,” she said.

But there are reasons to becautious. This is cancer, after all. Many other hoped-for miracleshave failed to materialize. This is a conference that has haileddrugs that extend lives by only a few weeks asbreakthroughs.

“We’re so used to failure, weget excited very easily,” said Dr. Kim Margolin, an expert onmelanoma and immune therapies at the Seattle Cancer CareAlliance.

Most of what is known about thePD-1 drugs is that they shrink tumors significantly in 15 to 50percent of patients. It is still not clearly established, thoughthere are some hints, that the drugs will let people livelonger.

And results seen in trials,under idealized conditions, do not translate perfectly to the realworld. One poster presented here looked at use in Britain ofYervoy, a melanoma drug approved in 2011 that disables a differentimmune system brake. Median survival has been only about half ofwhat was seen in clinical trials.

Moreover, just because the immune system is involved does not makesomething safe. Ask anyone with lupus, multiplesclerosis or other diseases caused byan aberrant immune system.

Yervoy, made by Bristol-Myers,has some serious side effects caused by overstimulation of theimmune system. The newer PD-1 drugs seem remarkably well toleratedso far, though lung inflammation is seen insome patients.

For the last decade or so, theemphasis in oncology has been so-called targeted therapy, in whichdrugs counteract particular genetic mutations that drive tumorgrowth. These were supposed to displace conventional chemotherapy,which tends to poison fast-growing cells, both cancerous andhealthy ones, causing serious side effects.

Targeted therapy has had somegreat successes, particularly the leukemia drug Gleevec. But cancercells, which tend to mutate rapidly, can develop resistance to thetargeted therapies. And it is becoming more difficult to developdrugs for each narrow population of patients with a particulartumor mutation.

The PD-1 drugs are in a sense areturn to a one-size-fits-all approach. And it might be harder forthe tumor to become resistant to the immune system, which canadapt, than to a single drug.

In fact, what most excitedresearchers here this weekend was “the tail.” When researchers ploton a graph how many patients remain alive over time, the curvestend to drop to near zero for metastatic cancer. A successful drugslows the rate of decline, but eventually almost all patients diefrom the cancer.

But with Yervoy and, expertshope, with the PD-1 drugs, there appears to be fraction of patientswho do not die of the disease, at least for a long time. The curvelevels out in a plateau.

Dr. Sznol said that of fivepatients treated at Yale with the Bristol-Myers PD-1 blocker,nivolumab, two had no evidence of recurrence even two years afterstopping the drug.

Over all, 133 melanoma patientsat various clinics took nivolumab in the Phase 1 trial. Mediansurvival was 16.8 months, with 62 percent of patients alive at oneyear and 43 percent alive after two years. There was no comparisongroup in the study, but with the existing melanoma drugs, about 24to 33 percent of patients are alive after two years, Dr. Sznolsaid.

So if the immune system is soeffective, why doesn’t it cure cancer on its own? One reason isthat cancerous cells are the body’s own cells, though mutated, andmight not be recognized by the immune system as foreign. Another isthat the tumors act to suppress the immune system.

Much of the previous attemptsat cancer immunotherapy have focused on the first problem — tryingto train the immune system to recognize the tumor and attackit.

The PD-1drugs tackle the second problem of immune systemsuppression. How many cancers this will work for is stillunclear. Much of the early work has been in melanoma, which isknown to be more susceptible than many other tumors to immunesystem attack. There are cases, though rare, in which the immunesystem vanquishes melanoma on its own.

What is encouraging doctors isthat the drugs can shrink some lung cancer tumors, which have notbeen considered particularly susceptible to immune attack. Thereare sporadic reports of cases with other cancers as well, likecolorectal cancer.