Nanovaults Used to Prod Immune System to Fight Cancer
Researchers at the University of California, Los Angeles (UCLA) 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 team leader Dr. Leonard Rome of UCLA.
"Researchers have been working for many years to develop effective immune therapies to treat cancer, with limited success," said Dr. 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.'" This work was published in the journal PLoS One.
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, Steven Dubinett, director of UCLA's 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; 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 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 Dr. Dubinett, who was a co-leader of the current study. "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 Dr. Sherven Sharma, the third co-leader of this study. In their Phase I study, the investigators found that 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," Dr. Sharma said.
"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," said Dubinett.
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, Dr. Rome said.
He 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 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, Dr. Rome added.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Novel CCL21-Vault Nanocapsule Intratumoral Delivery Inhibits Lung Cancer Growth ." An abstract of this paper is available at the journal's Web site.
Meanwhile, researchers at MIT have found a way to use nanoparticles to continually bathe engineered T cells with another set of growth-stimulating molecules known as interleukins (which themselves are part of the chemokine family). As a result, the immune cells, which are engineered to recognize a tumor as "foreign," continue to attack tumors instead of dying out, producing marked enhancement in tumor elimination in animals treated with the new combination therapy. Darrell Irvine of MIT led this study. He and his collaborators published the results of their experiments in the journal Nature Medicine.
Dr. Irvine and his team found that they could attach nanoparticles directly to engineered T cells without altering their immune system functions. In humans, T cells naturally attack tumors, but the tumors release molecules that weaken the T cells, rendering them harmless to the growing cancer. The researchers demonstrated that they could load the nanoparticles with interleukins, a family of molecules made by the immune system to stimulate T cell activity. The nanoparticles slowly release the interleukins, which counteracts the T cell inhibitory molecules produced by the tumor. Equally as important, the interleukins did not affect other nearby cells, which should limit potential side effects that might arise with the use of these powerful molecules.
In animal tests, the investigators found that mice with large established tumors died within 30 days when treated with engineered T cells attached to empty nanoparticles. In contrast, all the mice treated with engineered T cells attached to interleukin-loaded nanoparticles were alive 30 days after a single treatment.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Therapeutic cell engineering with surface-conjugated synthetic nanoparticles." An abstract of this paper is available at the journal's Web site.