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For a few brief months earlier this year, Dendreon’s Provenge looked like it might become the first cancer vaccine approved by the FDA, despite some iffy data supporting its effectiveness. The fate of Provenge now hangs in the balance following the FDA’s controversial decision to ask for additional data. But that hasn’t stopped Bellicum Pharmaceuticals from trying to improve on the work of its forbear.

(One quick note: Merck’s Gardasil and similar vaccines, which are frequently referred to as “cancer vaccines,” aren’t, really. These vaccines do what vaccines have always done, which is boost the body’s defenses against infection — in this case, by the human papilloma virus, which can cause cervical cancer. These vaccines don’t attack tumors directly.)

Cancer vaccines really don’t get much respect these days, after a series of high-profile failures and disappointments. The idea is simple enough: Use proteins unique to tumors to “train” the immune system so that it recognizes and attacks tumors, which normally skate past the body’s defenses like groupies waving backstage passes at a bouncer. But no cancer vaccine has ever worked unequivocally in human trials, as Dendreon’s experience with Provenge shows. At least Dendreon is still chugging along, though: Several other companies have gone down the tubes when their vaccines didn’t work, including all-but-forgotten names like CancerVax and Therion Biologics.

Enter Bellicum, a Houston biotech whose Latin name roughly translates as “call to war,” and whose strategy puts an interesting genetic twist on the basic notion of a cancer vaccine. (See our previous coverage in the sixth item here.) Like Dendreon, Bellicum’s basic strategy relies on dendritic cells, which are workhorses of the immune system that activate other defensive cells and teach them how to recognize invaders. (Tumors usually evade this system because, to the body’s watchdogs, they pretty much look like any other normal cell.)

To make Provenge, Dendreon extracts dendritic cells from a patient, marinates them with a protein “antigen” (that is, a molecule that stimulates an immune response) specific to prostate tumors, then re-infuses them into the patient. Theoretically, these newly primed dendritic cells will next begin recruiting an immune-cell army ready to have it out with any tumor cells they might encounter. Whether Provenge actually works or not, however, won’t really be known until an ongoing 500 patient trial produces some data, perhaps as early as next year.

Scientists at Houston-based Bellicum, however, think that process still has a number of shortcomings. Activated dendritic cells typically shut themselves off after about 24 hours and then die off another day later, limiting their ability to properly stimulate an immune response. That led a Baylor research team led by David Spencer — who is now also Bellicum’s chief scientific officer — to look for ways to either prolong that activation period or to “toggle” it so that the cells spent their entire activated lifetime in the lymph nodes, which are hotbeds for triggering immune reactions.

Those researchers focused on a dendritic-cell receptor protein — imagine sort of a docking port on the cell surface — called CD40, which is a sort of control switch for the dendritic-cell immune response. Normally, CD40 is only “switches on” when a dendritic cell docks with a particular type of T cell. The Baylor researchers, however, figured out how to genetically engineer a version of CD40 that could be switched on remotely by administering a particular drug molecule. If you’re interested, that team explained its work in a 2005 Nature Medicine paper that I’ve uploaded here (PDF).

The upshot of all this is that — theoretically, at least — Bellicum should be able to expose a patient’s dendritic cells to tumor antigens, genetically modify their CD40 receptors, return them to the patient and then switch them on once they’ve returned to the lymph nodes, thereby maximizing the dendritic-cell immune-stimulating effect. The process would look something like this:

To summarize, this slide shows dendritic cells (DCs) returned to the patient after modification and exposure to tumor antigens, where they migrate to the lymph nodes and activate killer T cells (formally known as cytotoxic T lymphocytes, or CTLs), which specialize in taking out infected cells. Here, the killer cells swarm tumors and destroy them. In theory, of course.

Bellicum says the system has worked well in animals and in laboratory tests using human dendritic cells, although it hasn’t yet tried the vaccine in humans. The company, however, hopes to move into early-stage tests in prostate-cancer patients by early next year.

Of course, no one knows if the strategy will work any better than other cancer vaccines, and there are certainly grounds for skepticism. There are an awful lot of moving parts in Bellicum’s vaccine-production process, which of course increases the chance that something unexpected will go wrong. What’s more, the immune system has a tendency to outfox even the most sophisticated attempts at manipulating it. Still, when in comes to opening up new avenues in the struggle against cancer, any attempt to refine what has so far been a disappointing strategy should probably be welcomed.

(UPDATED: See below.)

Catching up on a few life-science related items you may have missed over the weekend:

If you prick a cyborg, does he not bleed? — The WaPo’s Joel Garreau brings us this fascinating story about Peter Houghton, the first permananent recipient of a “left ventricular assist device” — a mechanical replacement for a failing chamber of his heart. Houghton’s heartbeat no longer goes lub-dub — instead, it whirrs as an impeller pushes blood through it. He has an electrical socket in his skull that connects his heart device to a camera bag filled with batteries. Worst of all, he’s become “less sympathetic in some ways,” he tells Garreau. “You’re an invented person trying to cope with it, trying to deal with the emotional context of it…. You become coldhearted. The thought doesn’t agree with me, the fact that it happens. But I don’t know what to do about it.”

The psychological problems of this latter-day cyborg are real, although as the story points out, no one knows if they’re the result of surviving a life-threatening illness, the machinery, the drugs Houghton must take, depression, advancing age or the absence of unknown hormones produced by the heart. Houghton spent some time contemplating suicide, but backed away in part because he couldn’t overcome his fear of actually choosing a method. (Antidepressants also seem to have helped.) He’s writing a book titled Cyborg Life and has even tried his hand at poetry:

A roller coaster.
Better than being dead, I think.
Three days out of five.

Provenge and the private eye — Pharmalot’s Ed Silverstein brings us the interesting tale of a plaintiff’s private investigator who stalked the editor of Cancer Letter, a newsletter that ran leaked letters critical of Dendreon’s cancer vaccine Provenge, which we’ve written about at length here and here. (The FDA asked Dendreon for more Provenge data, despite the previous endorsement of its advisory panel.) The plaintiffs — representatives for patients who want the FDA to reverse its Provenge decision — are now suing FDA officials and one of the two advisory-panel member whose critical letters ended up in Cancer Letter; they’re trying to figure out who leaked them to the newsletter.

Earmarking, a habit that’s hard to kick — The NYT’s Robert Pear reports a nice piece detailing how members of Congress — mostly Democrats, apparently — are steering Medicare money to select hospitals through the practice of “earmarking,” or inserting language that directs funding to a particular lucky recipient. Despite the Democratic leadership’s promise to make earmarking more transparent by listing them openly — something I’ve grappled with in a biotech-related context here — Pear found earmarks worth hundreds of millions of dollars hidden away in a House bill designed to expand health insurance for lower-income children.

Amgen’s Sharer called on to resign — Also from Pharmalot comes news of an Internet petition demanding the resignation of Amgen’s CEO, who has overseen a sharp decline in the biotech giant’s stock price amid accusations that the company has pushed overuse of anemia drugs which have been linked to various severe side effects. It’s likely to be about as effective as most Internet petitions, but it certainly doesn’t improve the climate for the embattled biotech.

American life expectancy outpaced by 20% of the globe — This AP story (courtesy of the Boston Globe) reminds us of a major cost of our dysfunctional healthcare system: We’re not living anywhere near as long as people in other countries. In fact, the U.S. has been sliding for years in global rankings of life expectancy. A baby born in the U.S. in 2004 can expect to live 77.9 years, ranking the U.S. 42nd in the world. Twenty years ago, we were 11th. UPDATE: Apparently we’re slipping in other respects as well. This WaPo story notes that Americans are no longer the world’s tallest people, either — the Dutch and other Europeans are now looking down on us. This observation isn’t entirely frivolous, either, since height is a proxy — albeit somewhat indirect, but still meaningful — for general health.

How to get, and keep, health insurance — Those not fortunate enough to work for a large company who provides health benefits already know that the individual-insurance market can be a scary place, at least if you’re not young and healthy. In most states, insurers have no compunction about denying you coverage for a variety of pre-existing conditions or if you take common prescription drugs, such as statins that lower “bad” cholesterol. What’s more, many insurers also ask if you’ve ever been denied insurance in the past, which if you answer truthfully — and lying is a bad idea — makes you a prime candidate for subsequent rejection again.

So it was quite a relief to find this LA Times advice on getting and keeping health insurance. Some of the advice is California-centric — it appears, for instance, that state law may require employers to extend your insurance for up to 36 months if you leave or are fired — but it’s still a good rundown of your rights and the pitfalls you can face in trying to protect your health and that of your family. For non-Golden State residents, there are plenty of other resources available — try, for instance, healthinsuranceinfo.net, which provides state-specific information compiled by the Georgetown Univeristy Health Policy Institute.

The first time you hear it, “evidence-based medicine” sounds like one of those goofily redundant phrases like “animated cartoon” or “past experience.” Aren’t doctors always carrying out studies of one sort or another? Isn’t medicine evidence-based already?

Well, no, not really. One of the biggest and least-understood problems in the U.S. healthcare system is that where many new drugs, medical devices and surgical techniques are concerned, there’s relatively little data as to which benefit patients most and under what circumstances. (See, for instance, today’s NYT column from David Leonhardt.) In part, that’s because there are relatively few incentives in today’s healthcare system for anyone to carry out such studies. For instance, it’s taken well over a decade to learn that unblocking partially clogged arteries fails to prevent heart attacks anywhere near as well as inexpensive drug treatment.

In principle, then, evidence-based medicine, which aims to scientifically measure and ultimately standardize medical practice systematically, sounds like something just about everyone could get behind. In practice, though, it all depends on whose ox — or ideology — is being gored by the evidence.

To see that, you don’t need to look any farther than the controversies that rage whenever the FDA rejects or postpones a drug approval for lack of sufficient evidence. Earlier this week, for instance, the NYT reported that two researchers who served on an FDA advisory panel received threatening e-mails and other messages after they opposed the approval of Provenge, a new type of “cancer vaccine” designed to trigger the body’s defenses against prostate tumors.

The researchers — Howard Scher of Memorial Sloan-Kettering Cancer Center and Maha Hussain of the University of Michigan — were concerned that the data offered by Provenge maker Dendreon didn’t actually prove that the vaccine worked. Although Scher and Hussain were in the minority when their panel voted to recommend approving Provenge, the FDA eventually concurred with the dissenters and said it would withhold approval until Dendreon produces more data.

To judge by the reaction, you’d think the FDA was having men with prostate cancer lined up and shot. My former WSJ colleague Marilyn Chase reported that “stunned” patient advocates vowed to deluge the agency with protest e-mails and to continue pushing for early access to the drug. One typical reaction came from Steve Fleischmann, a prostate-cancer survivor and advocate. “I feel very, very let down,” he told the WSJ. “What does this say to men who have prostate cancer and want to stay alive?”

Those were the measured reactions. A Sloan-Kettering spokeswoman told the NYT that Scher received phone calls and e-mails, including one titled “your murder.” Another letter writer told Scher, “You should get cancer.” Commenters on the WSJ Health Blog, whose three items on the FDA decision drew an outpouring of vitriolic attacks on Scher, Hussain and the FDA, accused the researchers of unethical behavior and FDA officials of shorting Dendreon’s stock or colluding with hedge funds. One commenter called the FDA decision “MASS MURDER” because it denied patients a promising drug.

It’s impossible not to empathize with people who consider Provenge the last hope for their loved ones or themselves. On the other hand, the evidence that Provenge actually works is slim indeed, while Dendreon seemed determined to spin it as hard as possible. (For a recap of the company’s incredible sloppiness with those clinical trials, see my earlier piece on Provenge.) In other words, Dendreon opportunistically took whichever path seemed to offer the quickest path to approval, even if it meant heaving a Hail Mary pass at the end. If patients really want to get angry at someone, they might want to take a closer look at Dendreon management — particularly CEO Mitchell Gold, who coincidentally sold off a big chunk of stock virtually the moment Dendreon shares bounced up on the positive advisory-panel vote.

Still, the patients consistently ask one question that deserves answering: Why not approve a drug that seems relatively safe, as Provenge does, and let it stand or fall in the market? While there’s a practical answer — the FDA is legally bound to ensure both the safety and effectiveness of drugs — a better response is both moral and economic.

No one wants prostate-cancer patients to die agonizing deaths. Allowing an unproven and undoubtedly expensive treatment like Provenge onto the market, however, means that its costs will be picked up by taxpayers and anyone who pays health-insurance premiums — again, in the absence of proof that it will help anyone. That seems like a bad gamble at a time when healthcare costs are already rising far faster than inflation. And since those skyrocketing costs are also boosting the ranks of the uninsured — partly because employers are scaling back coverage — you have to ask if providing an unproven treatment to a small group of cancer patients is worth the additional misery in store for ordinary people who lose or can’t get health insurance as a result.

In addition, once a treatment is available, it’s far more difficult to figure out whether it actually works or not. Patients aren’t likely to volunteer for controlled clinical trials in which they might end up receiving a dummy shot if they can be assured of getting the real thing from their doctor. While it’s still possible to compare marketed treatments to other marketed treatments, the logistics and expense can be hairy.

Patients, of course, aren’t the only ones grousing about the costs and delays that result from waiting for evidence that a given treatment works. Right around the time the FDA postponed approval of Provenge, for instance, the WSJ editorial page featured two pieces in which biotech-industry executives effectively argued for setting aside hard statistical evidence in favor of wishful thinking.

The first piece was by Richard Miller, the CEO of Pharmacyclics, a company that has been notoriously unsuccessful in proving that a drug called Xcytrin works against tumors in the brain the way it is supposed to. Miller’s complaint is that while clinical trials suggested that Xcytrin works, the data failed tests of “statistical significance” designed to distinguish actual results from random chance. Similarly, in a May 14 piece, a former FDA official named Mark Thornton lamented the day the agency postponed approval of Provenge and another cancer immunotherapy, calling it “Black Wednesday” and accusing the FDA of “kneeling before the altar of statistics.” (Oddly, the WSJ didn’t see fit to note that Thornton is currently a vice president at GenVec, a gene-therapy biotech that might also benefit should the FDA relax its statistical standards.)

The two men do have a point: The significance level required by the FDA is indeed arbitrary. The problem is that you have to set that bar somewhere, and Miller’s argument that it should depend on vague notions like “context” and “very real advances in science and medicine” is simply incoherent. (Thornton’s notion that “solid immunology science” should trump statistical significance isn’t any easier to understand.) My favorite part, though, is when Miller argues that “[s]tatistical standards, of course, should not be set aside” — this right in the middle of an article pleading with the agency to grant a statistical exemption for Xcytrin.

Such “up with patients, down with pointy-headed statisticians” sentiments have a politically conservative underpinning that isn’t hard to find. Check out, for instance, DrugWonks, a blog run by the Center for Medicine in the Public Interest. There, conservative pundit and former Manhattan Institute official Robert Goldberg criticizes the FDA’s “deadly decision to delay Provenge” and its advisors’ dedication to the “probabalistic priesthood” in language virtually identical to that used by Miller and Thornton — almost as if they’d all been reading from the same script. Ultimately, it’s hard to escape the impression that these folks are less concerned about patients than they are about the freedom to market drugs without all that pesky FDA interference.

On the other hand, every drug-safety scandal that erupts over treatments like Vioxx and Avandia helps make the case for the importance of good medical evidence. Among other encouraging signs that evidence-based medicine is slowly getting some traction are these articles on a House bill that would provide $3 billion for evidence-based studies by the federal Agency for Healthcare Research and Quality. AHRQ has fallen on hard times over the past decade, a trend that might be about to reverse itself. More on that in a future post.

(UPDATED: See below.) For almost two months, it has seemed that the FDA might be ready to approve an entirely new attack on cancer — a “cancer vaccine” that immunizes patients with tumor fragments in order to activate the body’s immune defenses against cancerous cells.

That dream suffered a major setback earlier today, when the FDA threw up a fresh roadblock to the approval of Dendreon’s Provenge, the first such cancer vaccine to go before the agency for regulatory approval. In March, an FDA advisory panel recommended approval of Provenge as a treatment for prostate cancer, despite some reservations about its efficacy in clinical trials. Instead, the FDA issued what is known as an “approvable” letter — a misnomer that actually means the agency won’t approve a drug’s application without additional data. Providing that sometimes requires additional lengthy and expensive clinical trials.

Although the near-term impact on Dendreon’s stock was severe — its shares plunged by 60 percent on the news — chances are good that Provenge or at least one of many other cancer vaccines now in clinical trials will eventually work. To explain why, I’ll set the stage in this post with a walk through the troubled history of cancer vaccines in general and Provenge in particular. In subsequent posts, I’ll take a look at other vaccines currently in late-stage trials and the efforts of venture companies in this area.

First, though, a quick note on terminology: This class of therapeutic cancer vaccines shouldn’t be confused with more traditional infectious-disease vaccines like Merck’s Gardasil. The Merck product protects against the human papilloma virus linked to cervical cancer, but isn’t really a “cancer vaccine” except in the loosest possible sense of the term.

One of the things that makes tumors dangerous is the way they evade the immune-system surveillance that guards against infection by bacteria and viruses. The goal of most cancer vaccines is to somehow stimulate the body’s defenders to identify tumor cells as enemy “others,” effectively calling in the immune system’s beat cops and strike teams to swarm and overwhelm them. (For a detailed description of how this should work in practice, click here.)

The problem has long been figuring out exactly how to trigger an immune response strong enough to attack the tumor but specific enough to leave other healthy parts of the body alone. There are two basic challenges: Identifying proteins specific to tumors that can be used to inoculate cancer patients, and finding the right way to expose those “antigens” to the guardians of the immune system.

Researchers have tried a variety of approaches, most of which have failed. In recent years, for instance, Antigenics has seen a cancer vaccine directed against “heat shock” proteins extracted from patients’ own tumors fail twice in large trials — once against kidney cancer, and again in skin cancer. A vaccine against pancreatic cancer made by Therion Biologics didn’t improve patient survival, effectively imploding the closely held company. Similarly, a startup called CancerVax pulled the plug on a melanoma vaccine in mid-2005 and later effectively vanished in a reverse merger with the European biotech Micromet.

Provenge, known generically as sipuleucel-T, took a different yet still relatively straightforward approach. Prostate-cancer patients underwent pheresis to filter out certain immune-system cells known as “antigen-presenting cells.” In the lab, researchers then cultured the cells together with a tumor protein called prostatic acid phosphatase in order to “prime” them for attack once they were reintroduced to the patient.

But Provenge’s history has been anything but smooth. The company’s first large-scale trial of the vaccine failed to demonstrate that the vaccine could hold prostate cancer in check, although Dendreon tried to argue that it appeared to work better in men with less aggressive prostate cancer — an after-the-fact analysis that amounted to moving the goalposts during the game. (For a technical summary of clinical-trial statistics and why Dendreon’s strategy didn’t hold water, click here.) The company rejiggered an existing trial to study Provenge’s effect in this particular subgroup of men, only to discover that a followup analysis of the original patients showed that men who received Provenge appeared to live longer than their counterparts. That analysis, however, involved just 127 men, a group so small that no one could be sure if the survival data was merely a statistical fluke.

Although the second trial also suggested that Provenge improved survival, it was also quite small and failed tests of statistical significance. What’s more, neither trial showed that the vaccine could actually slow the progress of the disease — a paradox that concerned experts assembled for an FDA advisory panel in March, although it nevertheless ended up recommending approval of Provenge by a 13-4 vote.

Dendreon’s shares shot up almost fivefold following that recommendation, although naysayers continued to warn that the vaccine hadn’t proven itself. Two no-voting members of the advisory panel wrote letters to FDA — which quickly leaked to the newsletter Cancer Letter — urging rejection of Provenge. In the end, the FDA apparently agreed, although it isn’t yet clear what sort of additional data the agency is looking for. Under one scenario, Dendreon may have to complete a large clinical trial that’s already underway, but which may not report data until 2010.

UPDATE: I’ve revised the description of Provenge’s clinical-trial history for accuracy.

Next: The outlook for other late-stage cancer vaccines.