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May 3, 2011

Investigators Bank on Chemokine-Loaded Nanovaults for Treating Lung Cancer

  • Scientists have demonstrated that recombinant versions of a cell's own vault nanocapsules can be used deliver the chemokine CCL21 as an approach to triggering immune system responses against  lung cancer. Studies by a team of researchers at multiple University of California, Los Angeles (UCLA) departments and institutes showed that treating lung cancer in mice using CCL21-loaded vault nanocapsules significantly reduced tumor size and burden.

    Results from the team’s murine lung cancer studies are published in PLoS One in a paper titled “Novel CCL21-Vault Nanocapsule Intratumoral Delivery Inhibits Lung Cancer Growth.”

    “In animals, the vault nanoparticles have proven to be as effective, if not more effective, than the dendritic cell approach,” states Leonard Rome, Ph.D., of the Jonsson Cancer Center and associate director of the California NanoSystems Institute. “Now we need to get the vault therapy approved by the FDA for use in humans.” Dr. Rome and his team hope to initiate human trials within the next three years.

    The UCLA research is founded on  promising data from an early clinical trial in which dendritic cells were engineered to over-secrete CCL21 and then directly injected into lung tumors. While the NCI-funded study has shown that this approach boosts the immune system's attack on tumors, the process of generating engineered dendritic cells from individual patients has variable success and is time-consuming and expensive, reports trial investigator Stephen M. Dubinett, M.D., director of the lung cancer program at UCLA’s Jonsson Comprehensive Cancer Center and a member of California NanoSystems Institute at UCLA.

    As an alternative delivery approach, the researchers, led by Dr. Dubinett and Dr. Rome, hit on the concept of using vault nanocapsules to deliver CCL21 directly into tumor cells. Vaults are cytoplasmic ubiquitous ribonucleoprotein particles that are highly stable in vitro, nonimmunogenic, and could potentially represent a flexible therapeutic delivery vehicle, Dr. Dubinett and colleagues report.

    Engineered in the baculovirus system, the particle self-assembles from a single expressed protein that can be modified to allow cell targeting, cell-specific endocytosis, and endosome penetration. Proteins and peptides fused to a vault-targeting domain are packaged in the particle, protected from the external environment, and released slowly at the target site.

    To evaluate the potential to use vaults as a vehicle for CCL21 against cancer, the authors packaged CCL21 into recombinant vaults and first confirmed that the resulting structures were biologically active using a chemotaxis assay. They were able to show that CCL21 retained its biological function when packaged in the recombinant vaults and that it induced the migration of T cells and dendritic cells.

    When they then administered CCL21-loaded vaults directly into lung cancer tumors in mice, the  animals demonstrated enhanced intratumoral leukocyte infiltrates comprising predominantly CD3-expressing T cells. Critically, the treatment led to significant decreases in tumor growth and reduced tumor burden by sevenfold compared to control animals, the researchers report.

    Further evaluation confirmed that the CCL21-loaded vaults induced systemic antitumor immune activity, as splenic T 10 cells taken from the treated mice demonstrated  augmented lytic activity against parental tumor cells in vitro.

    “This is the first study to describe that vault nanocapsules can be engineered to package and retain biologically active CCL21,” the authors note. “We anticipate that the use of vault nanoparticles will circumvent autologous dendritic cell preparation, minimize batch to batch variability, and allow for comparability and standardization.”


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