title: Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: A combination nanomedicine approach.
abstract: Therapeutic anticancer vaccine development must address a number of barriers to achieve successful tumor specific killing, including effective antigen presentation and antigen-specific T-cell activation to mediate cytotoxic cellular effects, inhibition of an immune-suppressive tumor microenvironment in order to facilitate and enhance CTL activity, and induction of memory T-cells to prolong tumor rejection. While traditional as well as modern vaccines rely upon delivery of both antigen and adjuvant, a variety of clinically relevant cancers lack ideal immunogenic antigens. Building upon recent efforts, we instead chose to exploit chemotherapy-induced apoptosis to allow for in situ antigen generation in a combination, nanomedicine-based approach. Specifically, lipid-coated cisplatin nanoparticles (LPC) and CpG-encapsulated liposomes (CpG-Lipo) were prepared for the temporally-controlled and multifaceted treatment of an advanced in vivo model of melanoma. Such combination therapy established strong synergistic effects, both in apoptotic extent and subsequent abrogation of tumor growth, which were due largely to both an enhanced cytotoxic T-cell recruitment and a reduction of immune-suppressive mediators in the microenvironments of both spleens and tumor. These results underlie a prolonged host lifespan in the combination approach (45 days) as compared with control (25 days, p < 0.02), providing promise toward a personalized approach to nanomedicine by establishing effect synergy in host-specific immunotherapy following chemotherapy.
authors.affiliation: The Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: The Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.affiliation: The Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Haynes
authors.affiliation: School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: gyxiang1968@hotmail.com.
authors.forename: Guangya
authors.initials: G
authors.lastname: Xiang
authors.affiliation: The Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: leafh@unc.edu.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000008:administration & dosage*; D018899:CpG Islands; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D007156:Immunologic Memory / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008081:Liposomes; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D050997:Nanomedicine / Q000379:methods*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D008081:Liposomes; D007371:Interferon-gamma; D002945:Cisplatin
keywords: Chemotherapy; Cisplatin nanoparticle; CpG-ODN; Immunotherapy; Melanoma