Mechanisms of immunization against cancer using chimeric antigens Journal Article
| Authors: | Engelhorn, M. E.; Guevara-Patiño, J. A.; Merghoub, T.; Liu, C.; Ferrone, C. R.; Rizzuto, G. A.; Cymerman, D. H.; Posnett, D. N.; Houghton, A. N.; Wolchok, J. D. |
| Article Title: | Mechanisms of immunization against cancer using chimeric antigens |
| Abstract: | Successful approaches to tumor immunotherapy must overcome the physiological state of tolerance of the immune system to self-tumor antigens. Immunization with appropriate variants of syngeneic antigens can achieve this. However, improvements in vaccine design are needed for efficient cancer immunotherapy. Here we explore nine different chimeric vaccine designs, in which the antigen of interest is expressed as an in-frame fusion with polypeptides that impact antigen processing or presentation. In DNA immunization experiments in mice, three of nine fusions elevated relevant CD8+ T-cell responses and tumor protection relative to an unfused melanoma antigen. These fusions were: Escherichia coli outer membrane protein A (OmpA), Pseudomonas aeruginosa exotoxin A, and VP22 protein of herpes simplex virus-1. The gains of immunogenicity conferred by the latter two are independent of epitope presentation by major histocompatibility complex class II (MHC II). This finding has positive implications for immunotherapy in individuals with CD4+ T-cell deficiencies. We present evidence that antigen instability is not a sine qua non condition for immunogenicity. Experiments using two additional melanoma antigens identified different optimal fusion partners, thereby indicating that the benefits of fusion vectors remain antigen specific. Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines. |
| Keywords: | controlled study; unclassified drug; nonhuman; antigen expression; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; mus; cancer immunotherapy; melanoma; animal experiment; animal model; protein binding; cercopithecus aethiops; cos cells; mice, inbred c57bl; antigen presentation; immune response; antigens, neoplasm; recombinant fusion proteins; cancer vaccine; cancer vaccines; antigen specificity; immunogenicity; escherichia coli; major histocompatibility antigen class 2; cancer immunization; vaccination; melanoma, experimental; dna vaccine; melanoma antigen; histocompatibility antigens class ii; herpes simplex virus 1; vaccines, dna; dna immunization; escherichia coli proteins; outer membrane protein a; protein vp22; bacterial outer membrane proteins; viral structural proteins; pseudomonas aeruginosa; exotoxin; exotoxin a; adp ribose transferases; bacterial toxins; exotoxins; virulence factors; human herpesvirus 1 |
| Journal Title: | Molecular Therapy |
| Volume: | 16 |
| Issue: | 4 |
| ISSN: | 1525-0016 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2008-01-01 |
| Start Page: | 773 |
| End Page: | 781 |
| Language: | English |
| DOI: | 10.1038/mt.2008.8 |
| PUBMED: | 18301399 |
| PROVIDER: | scopus |
| PMCID: | PMC4399381 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 8" - "Export Date: 17 November 2011" - "CODEN: MTOHC" - "Source: Scopus" |
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