Synthetic vaccine particles for durable cytolytic T lymphocyte responses and anti-tumor immunotherapy

• Published in: PloS one Vol. 13; no. 6; p. e0197694
• Main Authors: Ilyinskii, Petr O., Kovalev, Grigoriy I., O’Neil, Conlin P., Roy, Christopher J., Michaud, Alicia M., Drefs, Natalia M., Pechenkin, Mikhail A., Fu, Fen-ni, Johnston, Lloyd P. M., Ovchinnikov, Dmitry A., Kishimoto, Takashi Kei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2018; Public Library of Science (PLoS)
• Subjects: Adjuvants; Animal models; Animals; Antigen presentation; Antigen processing; Antigens; Biology and Life Sciences; Cancer; Cancer research; Cancer vaccines; Cancer Vaccines - administration & dosage; CD8 antigen; Cell Line, Tumor; Cervical cancer; Computer memory; Cytokines; Cytotoxicity; Dendritic cells; Deoxyribonucleic acid; DNA; Effector cells; Encapsulation; Female; Formulations; Health aspects; Human papillomavirus; Humans; Immune checkpoint; Immune response; Immunity, Cellular - drug effects; Immunity, Cellular - immunology; Immunization; Immunological memory; Immunosuppressive agents; Immunotherapy; Inflammation; Inoculation; Laboratory animals; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine and Health Sciences; Memory cells; Methods; Mice; Papillomavirus E7 Proteins - immunology; Peptides; Poly (I:C); Polyinosinic:polycytidylic acid; Polymers; Primates; Proteins; Research and Analysis Methods; Synthetic vaccines; T cells; T-Lymphocytes, Cytotoxic - immunology; Toll-Like Receptors - agonists; Toll-Like Receptors - immunology; Tumors; Vaccines; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - immunology; United States > US; Russia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0197694

We previously reported that synthetic vaccine particles (SVP) encapsulating antigens and TLR agonists resulted in augmentation of immune responses with minimal production of systemic inflammatory cytokines. Here we evaluated two different polymer formulations of SVP-encapsulated antigens and tested their ability to induce cytolytic T lymphocytes (CTL) in combination with SVP-encapsulated adjuvants. One formulation led to efficient antigen processing and cross-presentation, rapid and sustained CTL activity, and expansion of CD8+ T cell effector memory cells locally and centrally, which persisted for at least 1-2 years after a single immunization. SVP therapeutic dosing resulted in suppression of tumor growth and a substantial delay in mortality in several syngeneic mouse cancer models. Treatment with checkpoint inhibitors and/or cytotoxic drugs, while suboptimal on their own, showed considerable synergy with SVP immunization. SVP encapsulation of endosomal TLR agonists provided superior CTL induction, therapeutic benefit and/or improved safety profile compared to free adjuvants. SVP vaccines encapsulating mutated HPV-16 E7 and E6/E7 recombinant proteins led to induction of broad CTL activity and strong inhibition of TC-1 tumor growth, even when administered therapeutically 13-14 days after tumor inoculation in animals bearing palpable tumors. A pilot study in non-human primates showed that SVP-encapsulated E7/E6 adjuvanted with SVP-encapsulated poly(I:C) led to robust induction of antigen-specific T and B cell responses.