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.
