title: A therapeutic microparticle-based tumor lysate vaccine reduces spontaneous metastases in murine breast cancer.
abstract: Metastatic breast cancer is currently incurable, and available therapies are associated with severe toxicities. Induction of protective anti-tumor immunity is a promising therapeutic approach for disseminated breast cancer, as immune responses are (i) systemic; (ii) antigen-specific; and (iii) capable of generating long-lived "memory" populations that protect against future tumor recurrences. Pursuant with this approach, we have developed a novel heterologous prime/boost vaccination regimen that reduces spontaneous lung metastases in mice with established murine 4T1 adenocarcinoma breast tumors. In our studies, mice were orthotopically challenged with luciferase-expressing 4T1 tumor cells; luciferase expression was retained in vivo, enabling us to quantitatively track metastatic tumor growth via bioluminescent imaging. On day 6 post-challenge, mice received a therapeutic "prime" consisting of bulk tumor lysates encapsulated in poly(lactic-co-glycolic) acid (PLGA) microparticles (MPs). On day 11, mice received a "boost" composed of free tumor lysates plus a cocktail of Toll-like receptor (TLR)-stimulating adjuvants. Tumor progression was monitored in vaccinated and untreated mice for 25 days, a time at which 100% of untreated mice had detectable lung tumors. PLGA MPs injected subcutaneously trafficked to draining lymph nodes and were efficiently phagocytosed by dendritic cells (DCs) within 48 h. Our combination therapy reduced metastatic lung tumor burdens by 42% and did not induce autoimmunity. These findings illustrate that vaccines based upon MP delivery of tumor lysates can form the basis of an effective treatment for metastatic breast cancer and suggest that similar approaches may be both efficacious and well-tolerated in the clinic.
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, 52242, USA.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Gross
authors.forename: Amaraporn
authors.initials: A
authors.lastname: Wongrakpanich
authors.forename: Meghan B
authors.initials: MB
authors.lastname: Francis
authors.forename: Aliasger K
authors.initials: AK
authors.lastname: Salem
authors.forename: Lyse A
authors.initials: LA
authors.lastname: Norian
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001672:Biocompatible Materials / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D005260:Female; D019344:Lactic Acid / Q000737:chemistry; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008807:Mice, Inbred BALB C; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D001672:Biocompatible Materials; D019496:Cancer Vaccines; D004337:Drug Carriers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid