At the end of April, an FDA approval marked the end of a long regulatory road for an interesting drug with an even more interesting history: Provenge. Though it’s usually described as a vaccine for metastatic prostate cancer, that terminology is a bit misleading, as unlike traditional vaccines it doesn’t work by exposing an individual to an inactivated virus or a protective antigen. Instead, Provenge is more accurately the first “activated cellular immunotherapy,” a treatment where a patient’s own white blood cells are modified in a laboratory and re-infused to attack tumor cells. Though scientists have pursued this strategy for years, Provenge is the first product to reach the market after a tumultuous path that involved three separate randomized clinical trials.
Now that Provenge has been approved, a slow rollout of the treatment will begin in medical centers and urology clinics around the country. In the Chicago area, the University of Chicago Medical Center will be the first to offer Provenge, though treatment slots will initially be limited as the company behind the treatment, Dendreon, ramps up their capacity. Because of the press attention on the treatment’s novel mechanism, its controversial past, and the questions surrounding its slow debut, I visited with Russell Szmulewitz, an instructor of medicine who treats and studies prostate cancer for a Q&A session on Provenge.
Q: How does Provenge work?
A: Provenge is an activated cellular immunotherapy, which is a complicated way to say it is using your body’s own immune cells to target and fight your cancer. The process is labor-intensive, because it involves a process called apheresis, where patients are attached to a machine that’s sort of similar to a dialysis machine. But instead of cleansing your blood, it takes the white blood cells out of the blood and gives you back the red blood cells. Those white blood cells are then sent to the manufacturer at Dendreon, exposed to an activating protein, called PAP, which is a protein made by most prostate cancer cells, attached to a white blood cell growth factor called GM-CSF. The fused protein is incubated with the cells together, and what’s left is an activated cell product that’s called sipuleucel-T. That’s then shipped back to the treating physician and infused like a transfusion. The whole process is repeated every two weeks, for a total of three times.
It’s the first of its kind in terms of active immunotherapies. It’s not really a vaccine per se; a vaccine typically means injecting a patient with a protein and then your body has an immune response to that protein. This is quite different in that the cells are taken out of your body, futzed with, and given back to you.
Q: Who is Provenge meant for?
A: The label will be for minimally symptomatic, castrate-resistant, metastatic prostate cancer patients. These are patients who have failed standard hormonal manipulation, which we call castration, and have minimal symptoms from their disease. Obviously, that’s a bit subjective, but the studies that were done with this product were not done with patients who had severe pain from their malignancy or severe weight loss or things of that nature.
So if the patient fails hormonal therapy and then fractures a bone and has severe pain from their disease, this product is probably not indicated. That doesn’t mean it wouldn’t help them, we just don’t know, because that’s not the type of patient that was included in the studies. That being said it’s a huge population of patients.
Q: Why should doctors and patients be excited about Provenge?
A: It’s pretty non-toxic. Other than the fairly complicated apheresis procedure – 3 to 4 hours hooked up to this machine with a large IV – there’s really few, if any, severe toxicities. Some common things people get are fevers, chills, headaches, but that’s pretty much it in terms of side effects.
Because it’s a less-toxic, immune-based therapy, it’s gotten a lot of press. We’re excited because it works. It’s nice that it has limited toxicity, that’s for sure, but it seems to work.
In this disease state, it’s incurable. In fact, metastatic prostate cancer in general, even hormone-sensitive metastatic prostate cancer is incurable, so anything at this point in the game to improve quality of life, prolong life, meaningful life, those are the metrics you are judging success or failure by. It’s the first active cellular immunotherapy in cancer and especially in solid tumor malignancy, and it has a very different side effect profile than your typical cancer therapy.
Q: Why did it take so long to receive FDA approval?
A: Typically, when we do clinical trials for drug development, there’s phase I to see if its safe, phase II to see if there’s any disease activity and phase III to see if it has an impact on disease or a real, clinically meaningful impact. The company’s initial phase III trial showed a survival advantage; however, their primary endpoint statistically was disease progression, which is probably best termed a phase II endpoint. The FDA thus declined to approve the drug until further data became available. That was 2 to 3 years ago, and it caused a huge public outcry. Advocacy groups said ‘How can you deny us this drug? It works.’ So they went back and completed the larger phase III trial that was already in progress, which demonstrated a 4.1 month survival advantage, from about 21 months to about 25 months. That’s compared to standard chemotherapy, which prolonged survival from about 16 to 19 months. Four months is a big deal at this point in the disease, and that was highly significant.
Q: Why will Provenge be available to very few patients at first?
A: It’s important to know is that it can’t be done everywhere because of the apheresis issue and the fact that the company is quite limited in production. It’s not like a drug that you can just make more of. It’s a labor-intensive processing that will limit the number of patients that we’ll be able to do. So they’d rather be careful and make sure they have adequate capability to process everything. It’s going to be a big patient population that’s going to want this and will be eligible for this, so on some level we’ll have to work on optimally selecting the most appropriate patients that truly fit the characteristics of the study. Patients might have to be patient as things roll out.
There’s going to be two sites in the Chicagoland area that will infuse the product, but we’ll be the only ones doing it all. Our apheresis unit is across the hall from clinic where we see our patients, which is adjacent to the infusion center, so everything is right here for the patients. The doctors are here, and there’s oversight.
Q: What still needs to be resolved about the Provenge process?
A: There are a lot of questions going forward of figuring out who might benefit the most and how we can track benefit. Is there a way other than survival? Are there markers, immune markers or others that might give us a clue to know who’s going to benefit, who has benefitted prior to their death? And then there are logistical issues: How is this going to get billed and coded? They’re not quite sure, since this is not a typical chemotherapy, it’s not a transfusion, it’s not a vaccine, it is its own sort of entity. Because of the processing and apheresis that’s involved, it’s not cheap. It’s going to be very expensive, on the order of $100,000 for the full treatment course. Unlike a pill where a company will spend hundreds of millions in research and development and then you can churn them out, this actually requires a fair amount of labor. There are costs to apheresis, nursing supervision, it’s got to be shipped, processed, shipped back, and you have to make this fusion protein, which is also expensive. You can imagine the cost of it, and as of now it is not clear how much of the cost will be covered by insurers, including Medicare.
Q: With all those caveats, do you think people will still be interested in receiving the treatment?
A: I think people are going to be coming in, wanting to know if they can get this, even if we say this is not going to cure your disease. People hear immunotherapies and think non-toxic, and it is relatively non-toxic, but we’re talking about a 4-month survival advantage, it’s not a 3-year advantage. Patients go from 21 to 25 months, and that’s meaningful for sure, but it’s not a cure-all. We’re still excited about it and it’s definitely going to change the landscape of not just prostate cancer therapy, but also change the mindset of how people develop new therapies and think about developing new therapies. Now that we have demonstrated success in cellular immunotherapy for a solid tumor, we’ll have to see.