title: IL-12 delivered intratumorally by multilamellar liposomes reactivates memory T cells in human tumor microenvironments.
abstract: Using a novel loading technique, IL-12 is reported here to be efficiently encapsulated within large multilamellar liposomes. The preclinical efficacy of the cytokine loaded liposomes to deliver IL-12 into human tumors and to reactive tumor-associated T cells in situ is tested using a human tumor xenograft model. IL-12 is released in vivo from these liposomes in a biologically active form when injected into tumor xenografts that are established by the subcutaneous implantation of non-disrupted pieces of human lung, breast or ovarian tumors into immunodeficient mice. The histological architecture of the original tumor tissue, including tumor-associated leukocytes, tumor cells and stromal cells is preserved anatomically and the cells remain functionally responsive to cytokines in these xenografts. The local and sustained release of IL-12 into the tumor microenvironment reactivates tumor-associated quiescent effector memory T cells to proliferate, produce and release IFN-gamma resulting in the killing of tumor cells in situ. Very little IL-12 is detected in the serum of mice for up to 5 days after an intratumoral injection of the IL-12 liposomes. We conclude that IL-12 loaded large multilamellar liposomes provide a safe method for the local and sustained delivery of IL-12 to tumors and a therapeutically effective way of reactivating existing tumor-associated T cells in human solid tumor microenvironments. The potential of this local in situ T cell re-stimulation to induce a systemic anti-tumor immunity is discussed.
authors.affiliation: Department of Microbiology and Immunology and The Witebsky Center for Microbial Pathogenesis and Immunology, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Simpson-Abelson
authors.forename: Vivek S
authors.initials: VS
authors.lastname: Purohit
authors.forename: Wing Man
authors.initials: WM
authors.lastname: Pang
authors.forename: Vandana
authors.initials: V
authors.lastname: Iyer
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Todd L
authors.initials: TL
authors.lastname: Demmy
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Yokota
authors.forename: Jenni L
authors.initials: JL
authors.lastname: Loyall
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kelleher
authors.forename: Sathy
authors.initials: S
authors.lastname: Balu-Iyer
authors.forename: Richard B
authors.initials: RB
authors.lastname: Bankert
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D016503:Drug Delivery Systems; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D019394:Ki-67 Antigen / Q000032:analysis; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000097:blood / Q000276:immunology* / Q000628:therapy; D013050:Spectrometry, Fluorescence; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D019394:Ki-67 Antigen; D008081:Liposomes; D018664:Interleukin-12