A few short decades ago, cancer treatment consisted mainly of three pillars: surgery, radiation and chemotherapy. Although each has earned its place as a valuable option, more precise alternatives have long been the oncologist’s dream.
Now, a deeper understanding of the way our bodies fight disease is launching a promising new era in which cancer’s worst enemy may be the warrior within: our own immune system. By determining the characteristics of individual tumors at the genetic and molecular levels, researchers are tailoring treatment to each patient, aiming the built-in destructive power of the immune system directly at cancer.
A seismic shift
Until the early 2000s, researchers only dreamed that the immune system could be capable of keeping cancer at bay. Then research at Washington University and elsewhere began uncovering evidence that made the dream seem possible.
The shift began in 2001, when Washington University’s Robert D. Schreiber, PhD, and colleagues published a landmark paper in Nature concerning the adaptive immune system — the part of the immune system that recognizes and destroys specific disease-causing agents. They showed that mice lacking adaptive immunity developed more tumors, showing that conversely, healthy adaptive immunity restrains cancer development.
“The speed at which the center is translating groundbreaking discovery into new modalities of personalized treatment is incredibly exciting.”— Andrew M. Bursky, Trustee
His subsequent work demonstrated that tumors can evolve to evade and resist the adaptive immune response, which is why cancer can form in people with intact immunity. So, Schreiber surmised, if we could retrain the immune system to see cancer, we might have a new targeted tool to fight the disease. This research has advanced the latest frontier in cancer treatment: immunotherapy.
Schreiber leads the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, where he and many others are dedicated to translating human immunology research from the bench to the bedside. Much of their work has started in animal models. As he put it: “We’ve cured a lot of mice of their cancers.” But it’s not only mice who benefit from the center’s work.
“One of the things that’s been so exciting is that for the first time we have an opportunity to take what we’re learning at the bench level and see it applied to human disease,” said Schreiber, the Andrew M. and Jane M. Bursky Distinguished Professor. “That’s what’s so amazing about the Bursky Center.”
While Schreiber focuses on cancer, others at the center are applying findings about the immune system to autoimmune and infectious diseases, such as diabetes and the flu.
The center’s seminal cancer immunology research is beginning to move from the lab into the clinic, thanks to collaborations across the School of Medicine — and particularly with the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, where clinical researchers are working on a variety of ways to harness the immune system to fight cancer.
“Figuring out how to use the immune system to target cancer cells and not normal cells is something many of us have worked on for the last three or four decades,” said Timothy J. Eberlein, MD, the Spencer T. and Ann W. Olin Distinguished Professor, chair of the Department of Surgery and director of Siteman Cancer Center. “Now something we only dreamed about is becoming a reality.”
“The research being conducted at the Siteman Cancer Center is transforming the way the disease is treated.”— Alvin J. Siteman, Trustee Emeritus
One way to train the immune system to recognize cancer cells is by using a vaccine. Vaccines work by injecting parts of the foreign invader — in this case, cancer cells — into patients. The vaccine then prompts the immune system to mount an attack on that invader.
William E. Gillanders, MD, professor of surgery and Siteman Cancer Center research member, led one of the earliest human breast cancer vaccine trials. The vaccine contained a protein called mammaglobin-A, which is found at abnormally high levels in almost all breast cancer cells, making it an easy target for the immune system. Gillanders and Washington University colleagues were the first to study the protein in breast cancer and elicit an immune response to it, then developed the vaccine based on that work.
The trial results were promising, but mammaglobin-A also is made by certain normal cells and can generate an autoimmune response to them. So Gillanders, Schreiber and others began searching for other, more tumor-specific vaccine targets.
They found a candidate in proteins called neoantigens that exist on the surface of cancer cells. Neoantigens, which Schreiber was among the first researchers to recognize, are unique to each patient’s tumor but, importantly, are not present on normal cells. He and Gillanders reasoned that the immune system could be trained to recognize neoantigens as foreign and to destroy cancer cells without harming normal ones. But the challenge, said Schreiber, was how to identify each patient’s unique neoantigens and determine which were most likely to be recognized by the immune system.
This is where genome sequencing comes in. By sequencing patients’ cancer cell genomes and comparing them to their normal cell genomes, researchers can determine which neoantigens are unique to each patient’s tumor and which generate the strongest immune response. They can then use those neoantigens to make a personalized vaccine.
Gillanders’ group is testing neoantigen vaccines in patients with triple negative breast cancer, a form that is difficult to treat. They are conducting trials that combine the current standard of care — surgery, radiation and chemotherapy — with a vaccine in the hope of preventing recurrence.
“Finding the right way to combine traditional therapies with immune therapies such as vaccines, that’s where things are moving,” said Gillanders.
Neoantigen cancer vaccines represent a truly personalized treatment approach; neoantigens vary from patient to patient and from tumor to tumor, so each patient’s vaccine must be made from scratch. That can present challenges with production.
“There aren’t many places that can generate these products under the kinds of conditions that you need to make a vaccine,” said Schreiber.
Fortunately, the School of Medicine and Siteman Cancer Center are home to a Good Manufacturing Practice (GMP) lab, where immunotherapies such as cancer vaccines can be made and tested in clinical trials. Such facilities, which meet exceedingly high standards for consistency and quality, are not typical in most academic medical centers and help keep costs down when producing such expensive individualized treatments.
Sequence the genomes of the patient’s normal and cancer cells.
Using sequencing data, identify cancer cell neoantigens unique to the patient.
Make a vaccine with the neoantigens and inject into the patient.
Immune cells now see tumor cells as foreign and attack the cancer.
Deploying T cells
Another form of immunotherapy under investigation at the School of Medicine uses a patient’s T cells to target certain blood cancers, such as leukemia, lymphoma and multiple myeloma. T cells typically fight off disease. But in some cancer patients, these cells lose the ability to recognize and attack cancer cells.
“The immune system can’t always see cancer cells as threats; the T cells are sometimes blind to them,” said John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine in Oncology and deputy director of Siteman Cancer Center. “By modifying T cells, we tell them what to look for so they can go right to the leukemia or lymphoma and eliminate the cancerous cells.”
Like the cancer vaccines, this therapy is individualized for each patient and each tumor. The T cells, known as Chimeric Antigen Receptor, or CAR-T cells, are produced in the same GMP facility where the vaccines are made. They are designed and tested by the Center for Gene and Cellular Immunotherapy (CGCI) in the Department of Medicine’s Division of Oncology.
DiPersio and colleagues were involved in clinical trials that led to the Food and Drug Administration’s approval of CAR-T cell therapy, and Siteman Cancer Center is now among the first centers nationwide to offer it to patients. DiPersio’s team is now working on a way to make a universal form of CAR-T cells that can come from a donor rather than the patient. Such an approach could be faster, less costly and more effective for patients with rapidly progressing blood cancers. DiPersio and the CGCI team are attempting to expand application of current CAR-T to other diseases, such as T-cell leukemias and lymphomas, acute myelogenous leukemia and solid tumors.
“With the research that is being done, we are getting so close. The future looks brighter than ever before.”— Rodger O. Riney
Also entering the clinic is a new form of immunotherapy called checkpoint inhibitors. Checkpoints are proteins on the surface of T cells that survey proteins on other cells to determine whether they are normal or diseased. Normal cells are left alone, and diseased cells are flagged for destruction. Unfortunately, cancer cells can display proteins that bind to T cell checkpoints and trick the T cells so they do not see the cancer as foreign. Researchers are now devising antibodies that block the T cell-cancer cell interactions, making the cancer once again visible to the immune system.
The 2018 Nobel Prize in Physiology or Medicine went to James P. Allison, PhD, of the United States and Tasuku Honjo, MD, PhD, of Japan, who independently discovered two separate checkpoint inhibitor pathways. At Washington University, researchers are using checkpoint inhibitors in combination with traditional therapies as well as neoantigen vaccines in trials for breast, lung and other cancer types.
A new standard
Much of the work on targeted cancer immunotherapies could not have been done without the Elizabeth H. and James S. McDonnell III Genome Institute (MGI). In 2008, the institute led a historic effort to sequence the first entire cancer genome, of a woman with leukemia, and helped identify the genetic errors that contributed to her disease. Though it was an uncertain endeavor at the time, St. Louis philanthropist Alvin J. Siteman agreed to fund the project. That work has since established Washington University as a national leader in the field of cancer genomics and prompted many clinicians to add cancer genome sequencing to their standard of care.
“What appeals to us about the institute is its collaboration with St. Louis Children’s Hospital and the School of Medicine’s Department of Pediatrics in the application of genomics to pediatric cancers.”— James S. McDonnell III
A case in point: Nearly every patient with lung cancer who sees Ramaswamy Govindan, MD, the Anheuser-Busch Endowed Chair in Medical Oncology, gets some or all of their genome sequenced.
“We no longer stop at the microscopic level when diagnosing cancer,” said Govindan, co-leader of Siteman Cancer Center’s solid tumor program and a leader in lung cancer clinical trials and translational research. “Now we do molecular profiling and study the genes that are altered to see whether we can use targeted therapies.” Depending on the situation, that might involve using a targeted chemotherapy or customized tumor vaccine, either as part of a clinical trial or as a standard of care.
Govindan’s group is trying to understand the reasons why cancer cells metastasize or become unresponsive to medical therapies. He also is using sequencing to develop a neoantigen vaccine that he is testing in a trial for patients with non-small cell lung cancer, the most common form of the disease.
Collect patient’s T cells and engineer them to recognize and kill cancer.
Use antibodies that block cell interactions to restore immune destruction of tumors.
Use antibodies that attach to cancer cells to make them visible to the immune system.
Expose patient’s NK immune cells to chemicals called interleukins to help them better fight cancer.
Researchers at MGI and elsewhere at the School of Medicine are making key discoveries in a number of other cancer types, including leukemia, aggressive prostate cancer and estrogen receptor positive breast cancer, one of the most common forms of that disease. This work is helping to guide treatment decisions such as choosing the appropriate chemotherapy or determining who may be a good candidate for certain immunotherapies, such as vaccines.
MGI’s sequencing advances, the Bursky Center’s immunology discoveries and Siteman Cancer Center’s clinical prowess make for a powerful combination.
“The next frontier in cancer research is to apply our skills in genomics to better characterize the tumor, its environment and its interaction with the immune system,” said DiPersio. “That will be a huge help in understanding the relapsing and remitting of cancers.”
“The future is going to be pretty amazing for cancer patients. They’ll have more effective treatments with fewer side effects, more targeted therapies, early diagnosis and even ways to prevent the disease,” said Eberlein. “We’ve been fortunate to have the partnership of so many donors, patients and their families, who have recognized that investing in innovation and research is the future of cancer care.”
A focus on cancer disparities
One of the best ways to fight cancer is to stop it before it starts, and, failing that, make sure everyone has access to the best possible care. Siteman Cancer Center is working with the community in and around St. Louis to improve prevention and screening programs and to reduce cancer care disparities.
At the forefront of these efforts is Bettina Drake, PhD, MPH, associate director of cancer health equity for Siteman Cancer Center.
Drake, an associate professor of surgery in the Division of Public Health Sciences, began researching prostate cancer as a doctoral student at the University of South Carolina, in a state where African-American men are almost three times more likely to die of prostate cancer than white men — often due to missed diagnoses. The survival rate for prostate cancer, if caught early, is normally 95-100 percent.
Soon after her father was diagnosed with prostate cancer, Drake got involved in community outreach with area churches, providing educational materials about prevention and screening for those at risk of getting cancer. “The combination of my outreach experiences and my father’s diagnosis fueled my interest and passion in disparities research,” said Drake.
In St. Louis, Drake now leads the Prostate Cancer Community Partnership, part of the Program for the Elimination of Cancer Disparities at Siteman Cancer Center. The program seeks to eliminate screening and treatment barriers to improve patient outcomes. Drake works with community leaders and colleagues such as Lannis Hall, MD, MPH, Arnold D. Bullock, MD, and Aimee S. James, PhD, MPH, to develop public awareness campaigns and refine identification of high-risk groups. She is also focused on recruiting a more diverse patient population for Siteman clinical trials.
“When we do research, we want our patient population to resemble the people who will be receiving the treatment in the future,” said Drake.
Published in the Winter 2018/2019 issue