Peptide vaccine given with a Toll-like receptor agonist is effective for the treatment and prevention of spontaneous breast tumors.
Our goal is to develop peptide vaccines that stimulate tumor antigen-specific T-cell responses against frequently found cancers. Previous work has shown that to generate effective T-cell responses, peptides have to be administered in combination with strong adjuvants such as Toll-like receptor agonists. However, most animal tumor model systems used to study peptide vaccines were not truly representative of malignant diseases in humans because they solely used transplantable tumor lines, and instead of true tumor antigens, they used highly immunogenic foreign proteins. Here, we describe a peptide vaccination strategy, which is highly effective in delaying or preventing the occurrence of spontaneous breast tumors. Transgenic female BALB-neuT mice that carry the activated rat HER-2/neu oncogene were vaccinated with a synthetic peptide from the rat HER-2/neu gene product, which represents an epitope for CTLs in combination with a Toll-like receptor agonist adjuvant. Our results show that to obtain tumor antigen-specific CTL responses and antitumor effects, the vaccine had to be administered repetitively, or the function of CD4/CD25 T regulatory cells had to be blocked with anti-CD25 antibody therapy. Mice that were vaccinated with this approach remained tumor-free or were able to control spontaneous tumor growth and exhibited long-lasting CTL responses, not only against the immunizing peptide but also against other peptides derived from rat HER-2/neu product (i.e., epitope spreading). These results suggest that similar strategies should be followed for conducting clinical studies in patients.
Nava-Parada
Pilar
P
Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Forni
Guido
G
Knutson
Keith L
KL
Pease
Larry R
LR
Celis
Esteban
E
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D051193:Toll-Like Receptors