Dr. Vonderheide explores how boosting our body’s natural defenses could lead to new ways to prevent, treat, and even cure breast cancer
There are many remarkable ways that scientists globally seek to slow or cure not only breast cancer but all cancers. These treatments have delivered great successes, changing the way we diagnose and treat breast cancer. But what if we could suppress or even, perhaps, prevent such cancers in the first place?
Scientists are working to better understand the function of the immune system in breast cancer. The immune system is the body’s natural defense against foreign invaders––including cancer cells. Under normal circumstances, immune cells can recognize and attack abnormal cells, preventing cancer from developing. However, cancer cells are known to develop mechanisms that allow them to evade immune detection, which often leads to the growth and spread of tumors.
By further exploring how cancer interacts with the immune system and finding ways to bolster this natural defense, we move closer to a future where preventing or even curing breast cancer may one day be within our reach.
Dr. Robert Vonderheide sits at the intersection of immunology, oncology, research, and patient treatment. He is the director of the Abramson Cancer Center at the University of Pennsylvania and the John H. Glick, MD, Abramson Cancer Center’s Director Professor in the Perelman School of Medicine. Dr. Vonderheide also is a distinguished scientist and board-certified medical oncologist who has deciphered mechanisms of cancer immune surveillance and developed novel cancer therapeutics. His high-impact findings have been published in Nature, Science, Cell and the New England Journal of Medicine. He has been a BCRF Investigator since 2007.
Below is an edited transcript of their conversation.
Dr. Robert Vonderheide: In many cases we know that the immune system can attack cancer and make it go away, but the cancer is smart and … the immune system can get poisoned and can get suppressed or exhausted, literally exhausted and can’t get the job done and the tumors evolve in that setting. After that initial battle between the cancer cell and the immune cell, the cancer cell, if it wins, the one that grows out is much stronger and resistant to the immune system.
Dr. Vonderheide: So, the first efforts, and in fact, the efforts that are now standard of care for certain patients with breast cancer, get rid of those cancer-mediated immune suppression mechanisms, relieve the brakes on the system rather than stepping on the gas. And that’s been an incredible new way of treating patients with breast cancer and many other types of cancer. And for reasons that we’re not quite sure, maybe because the cancer cells are really even at the very beginning, avoiding the immune system, there isn’t an immune response, there isn’t a break to cut. And so now lately, really over the last five years, two years, work that we’re doing is to figure out how to turn on the immune system. So now stepping on the gas, these are vaccines and other types of stimulatory efforts and that have created a lot of excitement most recently for patients with breast cancer and other types of cancer.
Dr. Vonderheide: Chemotherapy has been used to cure thousands and thousands of women with early-stage breast cancer. So we’re not going to probably walk away from chemotherapy straight away. So, how can we now add immunotherapy and get it just right? We’ve learned there is a dynamic in biology. It changes. There’s a give and take and there’s a whack-a-mole going on and as soon as you put a biological pressure over on the left side, the tumor escapes on the right side. And it’s incredibly frustrating because that’s called resistance. We want to understand the molecules and the pathways and the interactions and that dynamic nature to model it mathematically and stop guessing and actually acting based on knowledge. I think we’re done making random chemotherapy and hoping it works. We’re making biologics, making immunotherapy, making vaccines. These are all based on biology, which requires often laboratory studies, and researchers, and a whole enterprise that itself is pretty dynamic.
Dr. Vonderheide: That’s a bunch of proteins that act as an enzyme that maintain the integrity of the tips of chromosomes. Humans have linear chromosomes, it’s all about preserving genomic, the integrity of the genes. The very ends of, so chromosomes are like shoelaces. They’re long wound up linear structures. And if they unravel, that’s a bad shoelace. So shoelaces have that little plastic thing on the end [aglets], that’s the telomere and telomerase creates that aglet. If you don’t have it, there’s no aglet. The shoelace unravels and it’s not functional. And we thought, I wonder if the immune system, if that’s identifiable. And it was. It is, it’s very clearly so, and that’s why you’re asking about it, it’s because based on that biology, we made a vaccine that targets that telomerase.
Dr. Vonderheide: Yeah, so we made those observations about telomerase in a laboratory setting and other labs saw that and checked our work over many years and added other insights. And at one point we said, “It’s time to see if this is true in humans.” And we ran a number of clinical trials where we found, yes, you can generate an immune response, you can do it safely. There seems to be a clinical benefit. Although, we had that was just more of a feeling than proof. So a breakthrough happened when we collaborated with a company here in the Philadelphia area called Inovio that was making DNA vaccines a very sophisticated, not your grandmother’s vaccine and molecularly based and was showing great promise in other situations, infectious disease. And we partnered with them to make a DNA vaccine against telomerase. And we tested that in a clinical trial with BCRF support for patients who had, had cancer. And we were vaccinating them to try to see if we could induce an immune response to prevent it from coming back.
Dr. Vonderheide: We’ve been working over the years developing this vaccine and we tend to meet patients who have cancer or who have advanced cancer. The very patients where the immune system has been suppressed. Now we’re understanding that this vaccine has a high safety profile, and we can bring it forward as a true prevention or sometimes we call it interception vaccine. It’s become, this steady work. But we were with a group of individuals the other day and they stopped me to say, “Wait a minute, I have goosebumps of what you’re saying. You’re vaccinating individuals against cancer the way you might vaccinate them against the flu to prevent this disease in the first place.” Yes, that’s what we’re doing. That’s what we want to do. We got a long road, but we’re moving. It’s pretty exciting.
Dr. Vonderheide: It’s to go to the next level with scale. So where the trial is nearly completed, we have to very, very carefully check not just the immediate side effects, but long-term side effects, super important. We need to understand the immune response and take samples back to the laboratory and just dissect them in every possible way. If all that is green lit, then we really need to think about how do we scale? Go from 50, 100 patients to 1,000 patients and we’re taking a hard look at the vaccine technology. Is it scalable? We need to design the studies where we can actually prove that cancer or early cancer lesions are being prevented. It’s like we’re a sports team and we want to win the Super Bowl, but we’re going to play the game in front of us first and not take our eye off that. But we definitely want to soon get to a much bigger stage.
Dr. Vonderheide: BCRF is focused on patients with breast cancer and those at risk. So there’s a real imperative to the work it does. For me, it provided a source of support that is unusual. One is it’s really cast as support for our work, our ideas. It’s not a contract. You do say what you’re going to do, but it’s really a we believe in you and let’s get this work done. And so it’s enduring. So that’s one thing. The second thing is that BCRF has collected a community of investigators of many disciplines that actually work as a community. There’s a kind of a, “Hey, are you a BCRF? You’re a BCRF investigator.” It’s like immediate street cred and an expectation that we’re going to collaborate even if you’re at different institutions. At the end of the meeting [BCRF’s annual research retreat], someone said, “Raise your hand if you’ve met someone and talked to someone at the meeting that has led to a new collaboration, something you weren’t doing on the plane ride here.” 75 percent of the hands went up, including mine. That’s the kind of organization. So it’s about the people. It’s not about the grant on the page, it’s about your ideas and your goal to eliminate breast cancer and do it as a community. So it’s very, very special and it has played a key role in the practical nature of my research, but also the inspiration of my research for many years. It’s just woven into me. I’m a BCRF investigator and hope I always will be.
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