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Home » Immunotherapies (IL-2, IL-15, PD-1s, etc.) » A brief history and explanation of IL-15

A brief history and explanation of IL-15

Posted by on May 3, 2012 in Immunotherapies (IL-2, IL-15, PD-1s, etc.), My Health Updates, Other Drugs, RCC News & Research - 14 Comments
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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.

Doctors Robert Waldmann and Kevin Conlon

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.

My Roommate

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 chris.battle@comcast.net.

  • Shaun T

    Chris, thanks for the great explanation. You are a true pioneer. The rest of the mRCC world is grateful for your courage and willingness to put yourself out there for us!

  • Vicki

    Go Chris Go – and wow what a team.  Glad to know that the SEs are not as bad as IL-2, but hoping you get even better results.  Give our regards to the Urology group – Pinto and the tall young guy – name escapes me, but my friends and I all called him Dr. Eye Candy .  Dr. Srinivasian was tremendous as well.  Keep up the good work, the tremdous updates and the good spirit.  All play together to bring you to good health. 

  • Matt Ivy

    Hang in there buddy.  You’re a special guy and the most important (non-primate) human I am following right now in Bethesda!  :)

    Maybe we will eventually meet if I end up dragging Tina up there for a test of her species/eligibility.

    Your Friend in Texas,
    Matt

  • Michele Becher

    Chris…thanks for being willing to go…literally…where almost no man has gone before. No guts, no glory as the saying goes!  This was a great article and you explained the drug and how it works very well.  Take care and say hi to Dena for us.  

    Todd and Michele Becher

  • Margo, Palm City, FL

    Very informative article, Chris!  Thanks so much for WHO you are and WHAT you are doing!  We are blessed to have you in our ranks.  Funny…the verse of an old song “look for the silver lining….” just came to mind!  Truly praying Mr. Chris Battle joins the IL-15 responder column.  Thinking of you, Dena and the girls.

    Margo

  • Mary Pattison

    What a nice summation of the information, thank you. So glad to hear that the side effects are not as severe as with former treatments.
    HOPE, yes and prayers for you to respond to this treatment!

  • Jane Kirby, Baltimore

    Chris, thanks for the information. I’m sure if we read Dr. Waldman’s article it would make no sense to most of us. I agree, iL-2 side effects were rough. I did the MDX-1106 and developed pneumonitis but once I went off the steroids from that, I was able to go back on MDX. It’s always fun to keep Dr. hammers on his toes :) . Anyway, I’ve had mixed results with MDX so I’m always checking out what may come next. Best of luck to you and thank you for keeping us so informed.

    • Chris Battle

      Thanks, Jane. I am a big fan of Dr. Hammers. And I agree, it IS fun to keep him on his toes. I don’t think he knew what to make of my sense of humor at first, but  he was soon cracking his own jokes in that German fashion of his! If this trial does not produce positive results, I’m sure we’ll be right back in Hans’ office discussing our next move.

  • Mrjackcoffee

    Great post and website.  Have you heard anything about “Three Months to Life” from Gerald White?  Not sure but others have ‘heard’ success with this guided imaging which sounds silly to me.

    • Chris Battle

      I have heard of Mr. White and read some of his observations, though in a limited nature. (I will have to look more closely.) There are opinions on both sides of the value of alternative therapies, though I’ve encountered few credible arguments for alternative therapy as the primary focus of treating cancer. However, one thing I’ve encountered in all of my various hospital stays (GW, Duke, Johns Hopkins, National Cancer Center) is support for the idea of psychoneuroimmunology, which is a focus on how the psychology (the power of the brain) affects your body’s natural physiology and immune system. Each of these hospitals — all top institutions in the nation — provided some form of psychological therapy to support the straight medical procedures. Often this was in the form of relaxation techniques, but guided imagery was also common. It was considered part of a holistic medical program, and it wasn’t administered by the oncologist but by somebody who specialized in the psychology of disease and wellness. But it was a part of the overall oncology division. The programs were always voluntary, but they were often encouraged as part of the healing process. I have participated in some to varying degrees. I spoke to one of the oncologists who discussed with me the existent research about the power of the mind to influence physiological outcomes — to a degree. The research is mixed, but there is encouraging data. Always, this was carefully framed in terms of supplemental care to the traditional medical therapies, just as exercise and healthy eating was always raised as part of a balanced approach to fighting cancer. Never were these psychological exercises suggested as lone approaches to battling cancer, and, to be honest, I haven’t read enough of White to know if he is suggesting guided imagery could take the place of medical therapy. (Certainly I would not agree with that.) What I learned, though, is that if somebody “gives up,” the brain can adapt to that fatalistic position to a degree. In other words: Somebody who takes the position that “I have cancer and I’m going to die” is more likely to have a tougher time than somebody who takes a determined attitude of living and fighting the disease. Again, this is on the margins — ultimately, I believe, the medical therapies are what will make the difference. That said, a positive mental approach can be helpful, and guided imagery can be a part of that.

  • Robert Waldmann

    Excellent article. My dad just told me about it. That would be Thomas Waldmann. He is indeed sharp as a tack. He did wonder if I could find a blog post on the web (he’s a big fan of google but considers blogs very new and obscure). Anyway his endorsement of the post is a sign of its quality as he knows a bit about IL-15. Also, I love the photo of your roommate.

    • Chris Battle

      Thanks so much for the good words, Robert. I’m flattered Dr. Waldmann found out about it. My wife, Dena, and I joked after meeting him the first time that it was like meeting a movie star –we’d ready up quite a bit on his career, the awards he’s won and his exciting work in developing this drug. I know he has plans to use it in combination therapy at some point, and I hope he gets that chance. Please tell him how much we appreciate everything he does.

  • Kristan Stacey-graf

    Thank you, I saw a post from Linda Cox on Face Book and just because I had time clicked on it. My husband Richard responded very well to the IL-2 in March of 2007. He has not had any growth or reoccurrence we praise God but have also always thought the only other option would be Sutent or nexavar….. I am so excited to see there are now other options!! From what I read so far on your blog it looks like it can be used for someone like my husband if it starts growing again? 

    • Dena Battle

      Kristan — both MDX-1106 and IL-15 might be options for you if Richard were to reccur — hopefully you won’t need either — but it’s a comfort to know that options are out there!  We’ll be praying that you never need them.  yours in hope, Dena

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