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Reprogramming Immune Response With Capsid-Optimized AAV6 Vectors for Immunotherapy of Cancer.

Abstract
In the current studies we generated novel capsid-optimized adeno-associated virus (AAV) serotype 6 (AAV6) vectors expressing a tumor-associated antigen, and assessed their ability to activate a protective T-cell response in an animal model. First, we showed that specific mutations in the AAV6 capsid increase the transduction efficiency of these vectors in mouse bone marrow-derived dendritic cells in vitro for approximately 5-fold compared with the wild-type (WT) AAV6 vectors. Next, we evaluated the ability of the mutant AAV6 vectors to initiate specific T-cell clone proliferation in vivo. Our data indicate that the intramuscular administration of AAV6-S663V+T492V vectors expressing ovalbumin (OVA) led to a strong activation (approximately 9%) of specific T cells in peripheral blood compared with AAV6-WT treated animals (<1%). These OVA-specific T cells have a superior killing ability against mouse prostate cancer cell line RM1 stably expressing the OVA antigen when propagated in vitro. Finally, we evaluated the ability of capsid-optimized AAV6-S663V+T492V vectors to initiate a protective anticancer immune response in vivo. Our results document the suppression of subcutaneous tumor growth in animals immunized with AAV6-S663V+T492V vectors expressing prostatic acid phosphatase (PAP) for approximately 4 weeks in comparison with 1 week and 2 weeks for the negative controls, AAV6-EGFP, and AAV6-WT-PAP treated mice, respectively. These studies suggest that successful inhibition of tumor growth in an animal model would set the stage for potential clinical application of the capsid-optimized AAV6-S663V+T492V vectors.
AuthorsMunjal Pandya, Kellee Britt, Brad Hoffman, Chen Ling, George V Aslanidi
JournalJournal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 38 Issue 7 Pg. 292-8 (Sep 2015) ISSN: 1537-4513 [Electronic] United States
PMID26261893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Capsid Proteins
  • Ovalbumin
Topics
  • Animals
  • Capsid (immunology)
  • Capsid Proteins (immunology)
  • Cell Line, Tumor
  • Dependovirus (immunology)
  • Genetic Therapy (methods)
  • Genetic Vectors (immunology)
  • Immunotherapy (methods)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms (immunology)
  • Ovalbumin (immunology)
  • Prostatic Neoplasms (immunology)
  • T-Lymphocytes (immunology)
  • Transduction, Genetic (methods)

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