title: Targeting the tumor microenvironment with anti-neu/anti-CD40 conjugated nanoparticles for the induction of antitumor immune responses.
abstract: Clinical and preclinical data indicate that immunotherapeutic interventions could induce immune responses capable of controlling or retard the tumor growth. However, immunotherapies need to be further optimized. We hypothesized that a more effective strategy for tumor eradication is to directly target the tumor microenvironment in order to generate a proinflammatory response and induce a localized antitumor immune response capable of eliminating the tumor cells. Nanoparticles have been proven to be an effective delivery system. In these studies we evaluated conjugated anti-RNEU and anti-CD40 antibodies onto PLA-(poly dl-lactic acid)-biodegradable nanoparticles (PLA-NP) for the induction of antitumor immune responses. The anti-neu/anti-CD40-NP were functional in vitro recognizing RNEU(+) tumors and activating dendritic cells. The delivery of anti-neu/anti-CD40-NP but not anti-neu-NP or anti-CD40-NP induced an antitumor response resulting in complete tumor elimination and generation of protective memory responses. The anti-neu/anti-CD40-NP specifically activated an antitumor response against RNEU(+) tumors but not against RNEU(-) tumors. The antitumor immune responses correlate with the induction of a Th1-proinflammatory response, reduction in the number of Tregs within the tumor and activation of a specific cytotoxic response. These results indicate that anti-neu/anti-CD40-NP with immunomodulatory properties are safe and can be used effectively as cancer vaccines strategy for the specific induction of antitumor immune responses.
authors.affiliation: Mayo Clinic College of Medicine, Department of Immunology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
authors.forename: Ana Lucia
authors.initials: AL
authors.lastname: Dominguez
authors.forename: Joseph
authors.initials: J
authors.lastname: Lustgarten
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D019013:CD40 Antigens / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D019344:Lactic Acid / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D011091:Polyesters; D011108:Polymers / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D019496:Cancer Vaccines; D016207:Cytokines; D019344:Lactic Acid; D011091:Polyesters; D011108:Polymers; D018719:Erb-b2 Receptor Tyrosine Kinases; C033616:poly(lactide); C524056:Erbb2 protein, mouse