A brief history and explanation of IL-15
Last week I touched briefly on the differences between IL-2 and IL-15, but I wanted to follow up with a little more information for those who might be interested in this trial and potential treatment option. I’ve had the chance to read some medical journal articles on IL-15 as well as chat with the two primary oncologists conducting the research here at the National Cancer Center.
History of IL-15
Dr. Kevin Conlon works with me on a daily basis and directly manages the patients and their care. He’s a tall man with an easy manner, unrushed in the way of so many oncologists. Perhaps this is because he doesn’t have a line of patients piling up in a waiting room as do oncologists at private hospitals. Whatever the case, it’s nice because he is willing to sit down and discuss in-depth the biology of IL-15, how it works and what’s going on in the broader research arena. Aside from that he puts a lot of personal energy into the care for his patients. He’s very attentive to any side effects I encounter. Equally important, he’s given thought to other trials and treatments at NCI should IL-15 not produce positive results. Dr. Thomas Waldmann is the chief of immunotherapy at NCI – and the Father of IL-15. At least, I have so designated him, as he co-discovered IL-15 in 1994 and has been the leading pioneer in its development as a cancer therapy. Dr. Waldmann first joined NCI in 1956. No, that is not a typo. Nineteen. Fifty. Six. His photo on the NCI website is in black and white. While I don’t work as closely with him as I do with Dr. Conlon, he has dropped by my room a couple of times. In his eighties now, he’s still hands-on as the prime investigator and clearly sharp as a tack. During his visits he’s usually accompanied by an entourage of young researchers. He, too, has been willing to sit down and talk with me about this drug and how it may work to fight cancer (as well as some infectious diseases) in humans.
You would think isolating and identifying the new cytokine would be the toughest part of bringing IL-15 to this stage of clinical research. I’m not sure that’s true, though. It’s been nearly twenty years since Waldmann discovered the molecule, and we are only just now beginning trials on human beings. This arduous path of trying to bring a new cancer therapy to market would be an interesting story in its own right – providing insights into the mindsets of risk-adverse pharmaceutical companies as well as the frustrating complexities of government bureaucracy. For some time, immunotherapy was the red-headed step-child of cancer research and development. There had been few breakthroughs. IL-2, for example, has been around for twenty years or so as an FDA-approved therapy, and while it has the potential of producing a durable response, that potential hovers around an eight percent chance of success. Moreover, it is a therapy that is only valuable to melanoma and kidney cancer patients. Since there are so few of us kidney cancer patients, there’s not a lot of profit potential to pharma companies to develop such drugs. Thank god melanoma is similar to kidney cancer in the way it reacts (and doesn’t react) to therapies; otherwise we kidney cancer patients would be ignored altogether. Until recently, there weren’t any other options for metastatic kidney cancer patients other than IL-2. Kidney cancer isn’t so rare that it qualifies for special government funding, but it is too rare to attract the attention of many private-sector drug companies. You don’t make a strong profit by developing drugs for only 3 percent of the cancer community. And there’s no large national advocacy movement of the sort you get with breast cancer, so there’s not much pressure on Congress to fund kidney cancer research.
After so many years of inaction, Waldmann and a team of researchers at NCI were eventually able to get funding from the government to develop clinical grade IL-15 in-house at NCI. It probably doesn’t hurt that IL-15 may also work with HIV and infectious diseases, but whatever it takes. After successes with research on mice, Waldmann began testing the drug on primates – also showing positive results. This led to FDA approval of taking the trials to the next level – using humans.
The protocol for the trial is one bolus (dose) of IL-15 for thirty minutes each day for twelve days in a row. (Yes, that’s a long stay as a guest of NCI.) As is the nature of a Phase I trial, Waldmann and Conlon have experimented with the dosing levels of the drug. Initially they started on a higher dose, which did result in some significant toxicities in the first few patients. As an NCI article put it:
Unexpectedly, however, human patients proved to be much more sensitive to the cytokine than primates, Waldmann said. “Even at the lowest dose, some patients developed fever and other side effects anywhere from two to four hours after a 30-minute infusion,” he said. “So we had to reduce the dose substantially.
Even this, however, paled in comparison to IL-2. As a patient in the trial currently, I’m now at a lower dose than that given to the initial participants. I can tell you that, at this level, the side effects are a cakewalk compared to Il-2. That said, the side effects are not unnoticeable. Like clockwork, about two hours after each infusion I definitely feel the effects: Flu-like muscle aches concentrated in the shoulders and arms, pretty stiff headaches, fatigue, loss of appetite, exacerbated cough (I brought the cough with me to the trial, but it is clearly aggravated by the drug) and a general feeling of … well, being hungover. Additionally, I have had some surges in my creatinine levels. Dr. Conlon doesn’t seem overly concerned, but he did note that my sensitivity is higher than other patients. Nobody really knows why; of course, that’s the point of a Phase I trial – to figure some of this stuff out and nail down a consistent drug schedule that can be applied to all patients.
Would I want to experience these side effects every day? No. I do think it would interfere with my normal quality of life – which at this time continues to include a mostly full-time work schedule. I would pretty much feel lousy every afternoon and start barking at colleagues and hurling cups of coffee during staff meetings. I only occasionally act that way now; doing it every day would get awkward. Still, would I be willing to endure them every day if the drug stopped or eliminated my cancer? Of course I would. Headaches on the one hand … death on the other … hmmmmm.
However, the point of immunotherapy is to spark your body’s natural reaction to viruses and pathogens. Presumably, if the IL-15 were effective, it would stop the cancer naturally and not require ongoing injections of IL-15. (Unlike biologic therapies like Sutent, which require continuous dosing for the life of the drug’s effectiveness.) Moreover, the great promise of IL-15 is that it targets memory T cells – meaning that the drug would remember the cancer and always attack it, thereby preventing recurrences in the future. More on that below.
Additionally, Dr. Conlon informed me that another protocol for IL-15 is also likely to be put into effect: Instead of daily dosing for twelve days, a new protocol will allow for ten days of continuous dosing. This may help maintain a more consistent level of distribution of the drug in the body. It also produces a stunning increase in the activation of T cells. Primate testing has shown an increase of T cells by a hundred-fold. He also noted, however, that it could lead to higher toxicities. Currently, the continuous dosing isn’t ready for primetime, but it’s on the near horizon. (Subcutaneous injections are also being investigated.)
The buzz around IL-15 is growing. During an immunotherapy event hosted by NCI a few years ago, researchers voted IL-15 as the most important immunotherapy agent to bring to clinical trials. Finally, they have. Indeed researchers are already looking beyond IL-15 as a standalone treatment and considering combination therapies, including vaccine therapy.
The Differences Between IL-2 and IL-15
Anyone who has undergone IL-2 is familiar with the side effects. Of course, they vary from individual to individual but can include chills, rigors, capillary leakage leading to edema (including the pulmonary), blood pressure spikes (as well as drops), heart rates spikes, rashes, skin peeling, fevers, aches, hallucinations, nausea, multiple gastrointestinal complications, kidney failure, neuropathy, and so miserably on and on.
There is a reason for these severe side effects. For one thing, as previously noted, IL-2 can be a fairly blunt instrument. It activates a more diverse range of immune receptors causing a broader array of immune-response side effects than IL-15. IL-15 is more refined in its targeting of Natural Killer Cells. However, as Dr. Waldmann explained, there’s another key distinction between IL-2 and IL-15, and one that contributes the harsh side effects of the former: IL-2 not only activates killer cells that go after pathogens ; it also regulates immune response, actually suppressing itself to avoid autoimmune disease – when the immune system can’t stop itself and keeps attacking and goes after healthy cells. (IL-2, basically, causes the pathogen-fighting cells to kill themselves after the job’s done – like little kamikaze cancer fighter pilots. The scientific term is less exciting: activation-induced cell death. ) The problem with this is that IL-2, in effect, shuts itself down. This is why high doses of the drug are necessary, contributing to far more severe side effects. Il-15, on the other hand, does not suppress immune response. It doesn’t shut itself down, and it inhibits IL-2’s role in activation-induced cell death. This allows for low-dose injections. Which results in fewer and less severe side effects.
Finally, there is one other key distinction between IL-2 and IL-15, perhaps the most important. IL-15 is unique in that it targets CD-8 T memory cells. Yeah, I know – CD-what? I don’t really know what the terminology means either, but Waldmann told me that what is important is that IL-15 not only stimulates natural killer cells to attack the cancer but cells that recognize and remember the cancer – forever. This means that, should the drug work as hoped, it would not only attack your cancer today; it would remember it and attack it again should it ever re-emerge. This means, in short, no recurrences. The potential to eliminate the cancer for good. (To read a more technical outline of how IL-15 impacts CD-8 read Waldmann’s journal article “The biology of interleukin-2 and interleukin-15: Implications for cancer therapy and vaccine design.”)
There are a lot of ifs in this post. There are a lot of ifs in this research. Only twelve patients have undergone this therapy before me, and the responses have been mixed. As often occurs, the drug has not acted in exactly the same way in humans as it did in mice and primates. Toxicity levels are higher. Degrees of lymphocyte stimulation are different. Some people experience liver toxicity, others don’t. As with me, some experience spikes in creatinine; others don’t. That said, previous research on “non-human primates” (I love that phrase) is convincing. And more importantly, there have been some positive results in the few patients so far tested.
There’s a lot of hope in this line of therapy, just as there is suddenly a lot more interest in immunotherapy as a whole. Even the big drug companies are waking up and getting in the mix – as Bristol-Myers Squibb backing MDX-1106 shows. With enough financial support – from both government and private-sector sources – we may launch into a new phase in the fight against cancer.
If you would like information on how to participate in this trial, feel free to contact me. I know that they are still recruiting and I would be happy to put you in touch with Dr. Conlon to determine if you qualify. You can leave a comment here, or if you would rather reach me privately my email is firstname.lastname@example.org.