Coencapsulation of tumor lysate and CpG-ODN in PLGA-microspheres enables successful immunotherapy of prostate carcinoma in TRAMP mice.
Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres (MS) deliver antigens and toll like receptor (TLR) ligands to antigen presenting cells (APC) in vitro and in vivo. PLGA-MS-microencapsulated model antigens are efficiently presented on MHC class I and II molecules of dendritic cells and stimulate strong cytotoxic and T helper cell responses enabling the eradication of pre-existing model tumors. The application of tumor lysates as a source of antigen for immunotherapy has so far not been very successful also due to a lack of suitable delivery systems. In this study we used PLGA-MS with co-encapsulated tumor lysates and CpG oligodeoxynucleotides (CpG-ODN) as well as microencapsulated polyI:C in order to elicit anti-tumor responses. Immunization of mice with such mixtures of MS yielded substantial cytotoxic T cell (CTL) responses and interfered with tumor growth in TRAMP mice, a pre-clinical transgenic mouse model of prostate carcinoma, which has previously resisted dendritic cell-based therapy. As an important step towards clinical application of PLGA-MS, we could show that γ-irradiation of PLGA-MS sterilized the MS, without reducing their efficacy in eliciting CTL and anti-tumor responses in subcutaneous tumor grafts. Since PLGA is approved for clinical application, sterilized PLGA-MS containing tumor lysates and TLR ligands hold promise as anti-tumor vaccines against prostate carcinoma in humans.
Division of Immunology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany. marc.mueller@uni-konstanz.de
Marc
M
Mueller
Wilfried
W
Reichardt
Julia
J
Koerner
Marcus
M
Groettrup
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D007114:Immunization; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011467:Prostate / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D004337:Drug Carriers; D009838:Oligodeoxyribonucleotides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid