Approach Devised to Trigger Immune System Using Nanovaults to Deliver Drugs

Preclinical studies in mice with lung cancer revealed that the protein stimulated the immune system to recognize and attack the cancer cells, potently inhibiting cancer growth, according to Dr. Leonard Rome, a researcher at UCLA's Jonsson Comprehensive Cancer Center, associate director of the California NanoSystems Institutes, and cosenior author of the study.

The study was published in the May 3, 2011, issue of the journal PLoS One, a peer-reviewed journal of the Public Library of Science. The new vault delivery system, which Dr. Rome characterized as "just a dream" three years ago, is based on a 10-year, on-going research effort focusing on using a patient's white blood cells to create dendritic cells, cells of the immune system that process antigen material and present it on the surface to other immune system cells. A phase I study that is part of the effort, led by UCLA's Dr. Steven Dubinett, used a replication-deficient adenovirus to infect the dendritic cells and prompt them to over-secrete CCL21, the first time the chemokine has been administered to humans. The engineered cells--10 million at a time--were then injected directly into the patient's lung cancer to stimulate an immune response.

The early phase study has shown the dendritic cell method is safe, has no side effects, and seems to boost the immune response--Dr. 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 to generate dendritic cells from the white blood cells and engineer them to over-secrete CCL21 is cumbersome, expensive, and time-consuming. It also requires a Good Manufacturing Practice (GMP) suite, a specialized laboratory critical for the safe growth and manipulation of cells, which many research institutions do not have.

"It gets complicated," said Dr. Dubinett, director of the Lung Cancer Program at UCLA's Jonsson Comprehensive Cancer Center, a professor of pathology and laboratory medicine, member of the California NanoSystems Institute (CNSI), and a cosenior author of the article. "You have to have a confluence of things happen--the patient has to be clinically eligible for the study and healthy enough to participate, 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, according to Dr. Sherven Sharma, a researcher at the California NanoSystems Institute, professor of pulmonary and critical care medicine, and cosenior author of the study. It was easier to isolate and grow the dendritic cells in some patients than in others, so results were not consistent.

In the phase I study, it takes more than a week to differentiate the white blood cells into dendritic cells and let them grow to the millions required for the therapy. The dendritic cells are infected with a virus modified to carry a gene that caused the cells to secrete CCL21 and then injected into the patient's tumor using guided imaging. "We thought if we could replace the dendritic cells with a nano-vehicle 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," Dr. Dubinett said.

The researchers plan to assess the vault delivery method in human studies within the next three years and hope the promising results found in the preclinical animal tumor models will be replicated. If such a study were 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 ultimately could be designed to be patient specific by adding the individual's tumor antigens into the vault, Dr. Dubinett reported. 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 hunt for and target tumors and metastases too small to be detected with imaging.

Dr. Rome cautioned that the vault work is at a much earlier stage than Dr. 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 FDA for use in humans."

Because a vault is naturally occurring particle, it causes no harm to the body and is potentially an ideal vehicle for use in delivery of personalized therapies, according to Dr. Rome.

Related Links:
University of California, Los Angeles
California NanoSystems Institute