Dr. Jonathan Cebon is director of the Joint Austin/Ludwig Institute for Cancer Research Medical Oncology Unit at Austin Hospital in Melbourne, Australia. There, he is overseeing several early-phase cancer vaccine clinical trials that seek to determine whether vaccination can prevent or significantly delay cancer recurrence in patients whose cancers are likely to come back after surgical removal of the primary tumor. Dr. Cebon was recently in New York City, where CRI caught up with him to ask about the exciting randomized phase II cancer vaccine clinical trial that has begun to accrue patients with malignant melanoma.
CRI: Dr. Cebon, your cancer vaccine research is generating a good amount of enthusiasm and high expectation.
Dr. Cebon: Indeed, the studies do seem to have captured quite a bit of attention. I think a lot of people are really interested in the cancer vaccine we’ve got, especially since we published in 2004 the data from our initial study, which yielded some surprising results. In that first trial, which we conducted back in 2001, we studied the effects of our cancer vaccine — composed of the protein NY-ESO-1 (which is expressed in many cancers but not in healthy tissue) and an adjuvant from CSL Limited called ISCOM™ — in cancer patients. The objective of that trial was to determine whether the vaccine was safe for humans and to measure what kind of effect, if any, it had on their immune systems. Some patients got the vaccine, and some got placebo. We learned that the vaccine was safe, even at the highest dosage, with no serious side effects, and that it did stimulate an immune response, particularly with elevated levels of NY-ESO-1-specific CD4+ and CD8+ T lymphocytes.
CRI: Did you see any reduction in the patients’ tumors?
Dr. Cebon: Most of these patients had already had their tumors removed surgically before the trial, so there were no actual tumors to study in this instance. Usually, however, some cancer cells escape surgery and, especially with the malignant melanomas, the cancers come back within two years — often sooner. We could see by examining blood samples taken from the patients during and after the study that patients who received the vaccine (instead of the placebo) showed evidence that their immune systems had learned to recognize the NY-ESO-1 epitopes, which means their natural defenses could — and probably did — target and destroy their cancers.
CRI: Does that mean the vaccine works?
Dr. Cebon: Well, phase I trials aren’t designed to answer whether a vaccine “works” or not; you need to run larger-scale tests in more patients before you’ll know that. But here’s the thing that surprised us and makes us feel that we really have something here: A while after the trial was over, an associate of mine in the lab called me over to look at some data. He’d noticed that most of the patients who’d received our vaccine were still cancer-free, two years after vaccination, while most of those who had received placebo had their cancers come back.
CRI: That is some strongly suggestive data. It looks like your vaccine is keeping these patients healthy.
Dr. Cebon: That seems to be the case, based on the data we have so far. But we won’t have stronger indications of that without running the phase II trial, which is designed specifically to find out whether the vaccine conveys direct clinical benefit on the patients.
CRI: How will the phase II trial prove the vaccine is helping patients?
Dr. Cebon: In this study, which is taking place at multiple sites across Australia, New Zealand, and the U.K., we’ve enrolled 100 patients (more than double the previous study), all of whom have had malignant melanomas surgically removed, and all of whom are at the same high risk for cancer recurrence. Half the patients are receiving the vaccine, and half are getting placebo. We’re following these patients for several years in order to track and compare patterns of cancer recurrence in the two groups. If the observation made in the first trial holds true, we should see clear evidence that patients receiving the vaccine remain cancer free significantly longer than those who received placebo.
CRI: When will you make the results of this trial available to the public?
Dr. Cebon: We’ll be able to see a correlation between vaccination and recurrence within 18 to 24 months, so by 2008 we should be ready to publish our findings.
CRI: What happens then if you get the positive results we’re all hoping for?
Dr. Cebon: Then we take it to larger-scale trials that will deliver the vaccine to many more cancer patients; we’ll also explore the vaccine’s effectiveness in other cancers; finally, we’ll look at variations in administering the NY-ESO-1/ISCOM™ vaccine. In fact, we’ve got another CVC trial going on that does just this.
CRI: You’re referring to CVC investigator Ian Davis’ trial at Austin/Health?
Dr. Cebon: That’s right. Ian is a colleague of mine who worked with me on the phase I trial. In that trial, we injected the vaccine into patients. In Ian’s pilot study, however, immune cells called dendritic cells (DC) are first separated out from the blood of cancer patients, treated with the NY-ESO-1/ISCOM™ and are then injected back into each patient. These DC are known to play a key role in the vaccine’s function by absorbing the NY-ESO-1/ISCOM™ vaccine particles and then breaking down the protein and moving to its surface portions of the protein, called peptides, which are then presented to other immune cells. These other cells then learn to recognize and destroy the cancer cells that also bear these peptides on their surfaces.
CRI: So, you’re first directly exposing the DC to the vaccine outside the patient — ex vivo pulsing — and then sending them back into the patient. What’s the possible advantage of this approach?
Dr. Cebon: We’ll be able to compare the results from Ian’s study to the other one to see which approach is more effective at stimulating an immune response. The DC response is critical to the function of the vaccine, and the more light we can shed on this process, the better our vaccines will work.
CRI: That will translate into more lives saved. Your patients must appreciate the good work you and your team are doing.
Dr. Cebon: They really do. I am a researcher and an administrator, but I’m also a doctor and I deal with patients every day. In many cases, we’re their last hope for survival. That’s a challenging position to be in, but it’s also very rewarding. And, you know, I’m always surprised at the positive attitudes my patients have. They know these are experimental medicines that might not always work, they know we don’t have the answers yet. If we did, we wouldn’t need to run these trials. Still, they come to our center, eager to participate in — and contribute to — cutting-edge science. Even if they don’t benefit, they know someone else will. I’m struck at how very frequently patients in our trials express those altruistic sentiments.
CRI: I’d like to talk about your trials within the context of the academically-driven Cancer Vaccine Collaborative. What makes this trial different from one that might be sponsored by a pharmaceutical company?
Dr. Cebon: Pharmaceutical company-funded trials are very effective at bringing drugs to the market; that’s what they’re designed to do, and they fill an important niche in this regard. However, traditionally, such trials are limited in their scope in terms of the questions they seek to answer and the science they seek to produce; in fact, they are driven ultimately by a product development plan, and the researchers involved in those studies have limited say in terms of setting the study’s objectives. CVC-funded trials, however, are discovery-driven and are underpinned by science — really good science, at that. CVC researchers have spent their entire careers seeking answers to fundamental science questions about the immune system. We want to understand the immunology first, and then we create therapies based on that understanding, rather than doing it the other way around, which is to create a product and then initiate trials designed to provide the scientific support needed to market the product. The CVC approach is different from pharma-supported research, and it provides much-needed support for a unique niche in academically supported clinical research that up until recently was much neglected.
CRI: In an article on the state of U.S. medical research, the Journal of the American Medical Association called attention to the imbalance between late-stage and early-stage research as well as the need for experts to work together to convert basic science into new therapies. In your opinion, does the CVC research model — with its support of early-stage, translational research and its demands for collaboration across many disciplines — alleviate this problem?
Dr. Cebon: It does. I tell you, none of the work we’re doing would be possible without collaboration. It takes an enormous amount of teamwork to run just one of these trials. Every step of the process, from developing and maintaining the vaccine, to delivering it to patients, to monitoring its effects and analyzing the resulting data requires the talent of many individuals and many partnering institutions. And the costs add up very quickly. These are not inexpensive studies. CRI’s financial support of these trials is indispensable, as is having access to the vast network of CVC scientists and clinicians, whose insight has proven invaluable time and again. I can speak for everyone who is a part of these trials — from the researchers to the patients — when I express just how grateful I am for CRI’s support and guidance.