UCLA scientists have discovered a way to "wake up" the immune system to fight cancer by delivering an immune system–stimulating protein in a nanoscale container called a vault directly into lung cancer tumors. The new method harnesses the body's natural defenses to fight disease growth.
The vaults, barrel-shaped nanoscale capsules found in the cytoplasm of all mammalian cells, were engineered to slowly release a protein — the chemokine CCL21 — into tumors. Pre-clinical studies in mice with lung cancer showed that the protein stimulated the immune system to recognize and attack cancer cells, potently inhibiting cancer growth, according to the study's co-senior author Leonard Rome, a researcher at UCLA's Jonsson Comprehensive Cancer Center and associate director of the California NanoSystems Institute (CNSI) at UCLA.
"Researchers have been working for many years to develop effective immune therapies to treat cancer, with limited success," said Rome, who has been studying vaults for decades. "In lung tumors, the immune system is down-regulated, and what we wanted to do was wake it up, find a way to have the cancer say to the immune system, 'Hey, I'm a tumor and I'm over here. Come get me.' "
The study appears in the May 3 issue of PLoS One, a peer-reviewed journal of the Public Library of Science.
Waking up the immune system
The new vault delivery system, which Rome characterized as "just a dream" three years ago, is based on a 10-year, ongoing research effort focused on using a patient's white blood cells to create dendritic cells, which are immune system cells that process antigen material and present it on their surface to other immune cells known as T cells, stimulating a response.
As part of that effort, Dr. Steven Dubinett, director of the Jonsson Cancer Center's lung cancer program, led a Phase I study in which these dendritic cells were infected with a replication-deficient adenovirus engineered to carry a gene that prompts them to over-secrete CCL21. The engineered cells were then injected, 10 million at a time, directly into patients' lung cancer tumors to stimulate an immune response — the first time the chemokine has been administered to humans.
The early-phase study has shown the dendritic cell method is safe, has no side effects and seems to boost the immune response; Dubinett and his team found T lymphocytes circulating in the blood stream with specific cytokine signatures, indicating that the lymphocytes were recognizing the cancer as a foreign invader.
However, the process of generating dendritic cells from white blood cells and engineering them to over-secrete CCL21 is cumbersome, expensive and time-consuming. It also requires a Good Manufacturing Practice (GMP) suite, a specialized laboratory that is critical for the safe growth and manipulation of cells, which many research institutions do not have.
"It gets complicated," said Dubinett, a professor of pathology and laboratory medicine, a member of the CNSI and a co-senior author of the current paper. "You have to have a confluence of things happen: The patient has to be clinically eligible for the study and healthy enough to participate, and we have to be able to grow the cells and then genetically modify them and give them back."
There also was the challenge of patient-to-patient variability, said co-senior author Sherven Sharma, a professor of pulmonary and critical care medicine and a researcher at the Jonsson Cancer Center and CNSI. It was easier to isolate and grow the dendritic cells in some patients than in others, so results were not consistent.
"We wanted to create a simpler way to develop an environment that would stimulate the immune system," Sharma said.
How nanovaults could be more effective, less expensive
In the Phase I study, it takes more than a week to differentiate the white blood cells into dendritic cells and let them grow into the millions required for the therapy. The dendritic cells are infected with the adenovirus and then injected into the patient's tumor using guided imaging.
"We thought if we could replace the dendritic cells with a nanovehicle to deliver the CCL21, we would have an easier and less expensive treatment that also could be used at institutions that don't have GMP," Dubinett said.
If successful, the vault delivery method would add a desperately needed weapon to the arsenal in the fight against lung cancer, which accounts for nearly one-third of all cancer deaths in the United States and kills 1 million people worldwide every year.
"It's crucial that we find new and more effective therapies to fight this deadly disease," Dubinett said. "Right now we don't have adequate options for therapies for advanced lung cancer."
The vault nanoparticles containing the CCL21 have been engineered to slowly release the protein into the tumor over time, producing an enduring immune response. Although the vaults protect the packed CCL21, they act like a time-release capsule, Rome said.
Rome, Dubinett and Sharma plan to test the vault delivery method in human studies within the next three years and hope the promising results they have found in pre-clinical animal tumor models will be replicated. If such a study is approved, it would be the first time a vault nanoparticle is used in humans for a cancer immunotherapy.
The vault nanoparticle would require only a single injection into the tumor because of the slow-release design, and it eventually could be designed to be patient-specific by adding the individual's tumor antigens into the vault, Dubinett said.
The vaults may also be targeted by adding antibodies to their surface that recognize receptors on the tumor. The injection could then be delivered into the blood stream and the vault would navigate to the tumor, a less invasive process that would be easier on the patients. The vault could also seek out and target tumors and metastases too small to be detected with imaging.
Rome cautioned that the vault work is at a much earlier stage than Dubinett's dendritic cell research, but he is encouraged by the early results. The goal is to develop an "off-the-shelf" therapy using vaults.
"In animals, the vault nanoparticles have proven to be as effective, if not more effective, than the dendritic cell approach," he said. "Now we need to get the vault therapy approved by the Food and Drug Administration for use in humans."
Because a vault is a naturally occurring particle, it causes no harm to the body and is potentially an ideal vehicle for use in the delivery of personalized therapies, Rome said.
The study was funded by a University of California Discovery Grant; a Jonsson Cancer Center fellowship grant; the National Institutes of Health; the UCLA Lung Cancer Program; U.S. Department of Veterans Affairs Medical Research Funds; and the University of California's Tobacco-related Disease Program Award.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2010, the center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 of the last 11 years.
The California NanoSystems Institute at UCLA is an integrated research facility located at UCLA and UC Santa Barbara. Its mission is to foster interdisciplinary collaborations in nanoscience and nanotechnology; to train a new generation of scientists, educators and technology leaders; to generate partnerships with industry; and to contribute to the economic development and the social well-being of California, the United States and the world. The CNSI was established in 2000 with $100 million from the state of California. An additional $850 million of support has come from federal research grants and industry funding. CNSI members are drawn from UCLA's College of Letters and Science, the David Geffen School of Medicine, the School of Dentistry, the School of Public Health and the Henry Samueli School of Engineering and Applied Science. They are engaged in measuring, modifying and manipulating atoms and molecules — the building blocks of our world. Their work is carried out in an integrated laboratory environment. This dynamic research setting has enhanced understanding of phenomena at the nanoscale and promises to produce important discoveries in health, energy, the environment and information technology.
Kim Irwin and Jennifer Marcus
Kim Irwin and Jennifer Marcus