title: Novel CCL21-vault nanocapsule intratumoral delivery inhibits lung cancer growth.
abstract: BACKGROUND
  Based on our preclinical findings, we are assessing the efficacy of intratumoral injection of dendritic cells (DC) transduced with an adenoviral vector expressing the secondary lymphoid chemokine (CCL21) gene (Ad-CCL21-DC) in a phase I trial in advanced non-small cell lung cancer (NSCLC). While this approach shows immune enhancement, the preparation of autologous DC for CCL21 genetic modification is cumbersome, expensive and time consuming. We are evaluating a non-DC based approach which utilizes vault nanoparticles for intratumoral CCL21 delivery to mediate antitumor activity in lung cancer.
  
  
  RESULTS
  Here we describe that vault nanocapsule platform for CCL21 delivery elicits antitumor activity with inhibition of lung cancer growth. Vault nanocapsule packaged CCL21 (CCL21-vaults) demonstrated functional activity in chemotactic and antigen presenting activity assays. Recombinant vaults impacted chemotactic migration of T cells and this effect was predominantly CCL21 dependent as CCL21 neutralization abrogated the CCL21 mediated enhancement in chemotaxis. Intratumoral administration of CCL21-vaults in mice bearing lung cancer enhanced leukocytic infiltrates (CXCR3(+)T, CCR7(+)T, IFNγ(+)T lymphocytes, DEC205(+) DC), inhibited lung cancer tumor growth and reduced the frequencies of immune suppressive cells [myeloid derived suppressor cells (MDSC), T regulatory cells (Treg), IL-10 T cells]. CCL21-vaults induced systemic antitumor responses by augmenting splenic T cell lytic activity against parental tumor cells.
  
  
  CONCLUSIONS
  This study demonstrates that the vault nanocapsule can efficiently deliver CCL21 to sustain antitumor activity and inhibit lung cancer growth. The vault nanocapsule can serve as an "off the shelf" approach to deliver antitumor cytokines to treat a broad range of malignancies.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Upendra K
authors.initials: UK
authors.lastname: Kar
authors.forename: Minu K
authors.initials: MK
authors.lastname: Srivastava
authors.forename: Asa
authors.initials: A
authors.lastname: Andersson
authors.forename: Felicita
authors.initials: F
authors.lastname: Baratelli
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Kickhoefer
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Rome
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D054421:Chemokine CCL21 / Q000378:metabolism*; D002633:Chemotaxis; D003713:Dendritic Cells / Q000166:cytology; D016503:Drug Delivery Systems; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007107:Immune System; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules; D036103:Nanotechnology / Q000379:methods*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; C515478:CCL21 protein, human; D054421:Chemokine CCL21; D053769:Nanocapsules; D049452:Green Fluorescent Proteins