David Avigan, M.D.
Like most physician–scientists, David Avigan, M.D., leads a double life. On the one hand, he manages the care of patients undergoing some of the most intensive cancer treatments as the director of the Hematologic Malignancy and Bone Marrow Transplant Program at Beth Israel Deaconess Medical Center. On the other, he works assiduously in the laboratory as the director of BIDMC’s cancer vaccine initiative to find new ways to harness the human immune system to fight off those same malignancies. “There’s a real personal sense of accomplishment with helping people, not only by giving them medications but really supporting them through the course of their treatment. And there’s the excitement of sitting in the lab with our group trying to think of new scientific ideas,” says Avigan. “Those are both aspects of my life. But at the end of the day, it’s the struggle of integrating those things that is most meaningful to me and what I find most ennobling. I feel like we struggle every day to get it right.”
Avigan is aided in this struggle by the fact that the immune system—the body’s internal machinery for fighting off disease—provides a natural bridge between the clinical and research sides of his work. Interested in blood cancers like leukemias and lymphomas from early in his career, Avigan focused his initial training on bone marrow transplantation (BMT), which was one of the first ways physicians learned to exploit the immune system to target these cancers in a clinically meaningful way. Bone marrow is the spongy tissue in the core of our bones that gives rise to blood cells and other key players in our immune response. In this risky procedure, recipients receive blood-forming stem cells harvested from healthy donors to restore the function of their bone marrow after having their immune system destroyed with massive amounts of chemotherapy or radiation. “Initially people thought of BMT as curing the disease with high doses of chemotherapy and then giving patients donor stem cells as just a way of helping them recover afterwards,” notes Avigan. “Then came the discovery that the immunologic relationship between the donor and the recipient actually played a critical role—perhaps the critical role—in preventing relapse, and it created this excitement about whether one could target a more specific immune response against the disease.”
For the last 15 years, Avigan has built an entire research program at BIDMC around this exciting concept. While colloquially called a cancer vaccine initiative, it is not based on our traditional notion of vaccination which centers on prevention. Rather than protecting against infection, Avigan’s vaccines are therapeutic, designed to train the immune system to recognize cancers as foreign and to attack them as it would any other disease or harmful invader. The initiative is making significant inroads in this type of personalized cancer treatment, and Avigan hopes that the stellar work of his team will get greater visibility as a result. “This is a signature program for us—we are now one of the leading vaccine centers in the world,” he says. “But I think it is a bit of a hidden jewel, even among the BIDMC community.”
The time appears to be ripe for drawing more attention to and investment in cancer vaccines. Clinical immunotherapy is a field coming into its own, and BIDMC’s vaccine group is right on the leading edge of discovery. Cancer is very effective at flying under the immune system’s radar, allowing it to run rampant through the body, but science and technology are now starting to catch on to how the disease performs its deadly covert operation. “The key to making an effective cancer vaccine is understanding the wiliness of the tumor cell and really trying to outsmart it,” says Avigan. “In the last 10 years, we have gained a much more sophisticated understanding of the relationship between the immune system and cancer, both what the cancer cells do to promote tolerance and diminish the immune system’s activity and how we might activate the immune system to selectively overcome that dynamic. I think there’s been a real revolution in that.”
One of the critical elements fueling this revolution has been the discovery of dendritic cells and the development of the science behind them. These cells are now recognized as powerful teachers of the immune system, responsible for educating the body on what belongs and what doesn’t belong within its confines. Avigan has seized on the idea of exploiting the capacity of dendritic cells to retrain the immune system so that it recognizes that cancer is something that absolutely shouldn’t be in the body while keeping intact all the things that should. “Much of the struggle we have with chemotherapy is that it doesn’t do a good job a lot of the time distinguishing normal, healthy tissue, particularly rapidly dividing normal tissue, from cancer cells,” says Avigan. “What we hope to do with a vaccine is to use the selectivity of the immune system to create a therapy that is not only effective against the cancer but less toxic to the person getting the treatment.”
As the first step in this process, Avigan’s team took cells from a patient’s tumor and blended them chemically with dendritic cells generated from the same patient, creating what is called a hybridoma, or fused cell. The resulting hybridoma, which forms the basis of the vaccine, has the wide range of cancer-specific proteins, including those specific to that particular patient, combined with the immune-stimulating machinery of the dendritic cells. “What we saw in this model was that the level of immune responsiveness was far more dramatic than what we were seeing when we just used individual tumor proteins,” says Avigan, noting that they are one of the only research groups in the world using this fused-cell strategy. “We were generating a much broader response, which in pre-clinical models was very potent and caused the regression of metastatic disease—where the cancer has spread—in animals.” They also saw similar responses against human tumor cells in vitro.
With such promising results, Avigan was, of course, eager to see how the hybridoma model might play out in real patients. Phase 1 clinical trials, which test the safety and feasibility of a treatment, soon followed. In these studies, the team used the vaccine to treat patients with latestage myeloma, kidney cancer, and breast cancer, for whom most traditional therapeutic options had been exhausted. Overall, the vaccine was well tolerated and stimulated an immune response against the tumor cells; in the advanced myeloma study, about 70 percent of patients saw a prolonged period of stability in their disease with minimal side effects. Avigan’s group subsequently embarked on Phase 2 studies to examine whether the vaccine might be even more effective as a way to target the cancer remaining in patients with earlier-stage disease after treatment with more conventional therapies, such as BMT or chemotherapy. They showed that vaccinating myeloma patients post-BMT resulted in a near doubling of those who achieved a complete therapeutic response. In an ongoing study of patients with acute leukemia, vaccination after chemotherapy helped maintain remission in nearly 70 percent of patients. Ultimately, the team’s progress has been so encouraging that the hybridoma treatment was selected for a first-of-its-kind national trial involving 10 leading cancer centers whose researchers will convene at BIDMC for training on how to generate the vaccine.
But Avigan knows that their work has only just begun. Although they have had dramatic results at the outset, the team realizes that they need to perfect their understanding of how cancer avoids the immune system so that it can’t just reset the immune response and ultimately escape the vaccine. They are currently investigating a new antibody, which blocks a pathway hijacked by tumors or chronic infections to promote tolerance, to see if it might boost the effects of the vaccine. But at the same time, they need to be careful not to heighten the immune response so much that it starts attacking more than just the cancer. “We’ve been moving back and forth between the lab and the clinic to see how we can create this immune response and make it sustainable, and reverse tumor-mediated immune suppression but not do it to a point where patients start to get autoimmune disease,” says Avigan. “That balance is the whole critical juncture here.” The team also hopes to move their therapy into Phase 3 studies to look at the vaccine in conjunction with standard treatment compared to standard treatment alone to define what impact the vaccine might have on long-term outcomes and, most importantly, survival.
But all this formidable research requires formidable financial support. Avigan stresses that individual philanthropy to cover line items not subsidized by federal grants—including generous gifts from Arthur R. Hilsinger and Barbara J. Janson, Edythe I. Kames, Susan S. and Paul Weisman , and the late Melvin Small and his wife, Sarah—has been a “godsend.” He has also been personally moved by donations from grateful patients like Howard Bleich and Howard Marton to support his work. However, he knows that his team will still need an influx of funding to realize their ultimate vision for the cancer vaccine initiative. For example, the scale of typical Phase 3 studies requires a much larger facility than the existing one at BIDMC, and Avigan firmly believes that his work is not something a program of their caliber should be farming out. “There’s a lot of need both in terms of providing infrastructure for the program and providing the bricks and mortar for an actual facility expansion,” he says. Avigan also points out that this may be the best time for philanthropists to have a tangible impact on the future of cancer treatment. “It’s not like we think this is a really cool model in the lab and we hope it works,” he asserts. “We’ve now treated a few hundred patients across several different diseases and have seen potent clinical responses. This idea has matured into a potential therapeutic area of development that may make a huge difference for patients.”
And, for Avigan and his colleagues, that’s what it is all about—their patients. Because most of his team works at both the bench and the bedside, Avigan says there is a whole psychology behind their research that is predicated on their work as clinicians. Blood cancer physicians have the added unique perspective of treating their patients for extended periods of time; as a consequence, they become close to their families and invested in their lives. Because their treatments all too often prove inadequate, they still see their patients succumb to their disease despite all their best efforts. That is something Avigan hopes his cancer vaccine initiative will change. “We take care of patients that are very near and dear to us; they are our responsibility both when things go right and when things go wrong,” he says. “In the clinic, we become acutely aware and humbled by the fact that whatever advances we have made still fall short of where we want to be. We see both the power and the difficulty of that and what it poses for our patients. We can see what a difference it can make for them and how far we still have to go. And that’s what drives us.”