Therapeutic vaccination halts disease progression in BALB-neuT mice: the amplitude of elicited immune response is predictive of vaccine efficacy.
The aim of this study was to evaluate the efficacy of genetic vaccination with rat ErbB2 antigen in a therapeutic setting for the BALB-neuT mouse model of mammary carcinoma and to establish immunological correlates with vaccine efficacy. To define an early therapeutic setting we performed imaging studies of mouse mammary glands with a high-frequency ultrasound system that allowed the diagnosis of tumor lesions before they become palpable, starting from week 13 after mouse births. An intensive immunization protocol of vaccination was implemented at this stage, consisting of four weekly DNA injections with electroporation followed by two injections of adenovirus carrying the codon usage-optimized cDNA encoding the extracellular-transmembrane domain of rat ErbB2. Immunological parameters were monitored in each individual mouse by analyzing peripheral blood leukocytes. The appearance of the first palpable tumor in vaccinated mice was delayed and there was a statistically significant time gap before additional masses developed, indicating disease stabilization. As a result of the immunization, antibodies and CD8(+) T cells to rat ErbB2 were detected and the amplitude of elicited responses correlated with the efficacy of vaccination. Moreover, the vaccination regimen specifically halted the rise in circulating myeloid suppressor cells (MSCs). All three parameters, that is, CD8(+) T cells, antibodies to rat ErbB2, and circulating MSCs, measured at the end of vaccination could be used as predictive biomarkers for future tumor development. This study emphasizes the potential of genetic vaccines for the therapeutic treatment of malignancies and suggests possible predictive biomarkers to be further validated in the clinic for the follow-up of vaccinated cancer patients.
Department of Oncology, Istituto di Ricerche di Biologia Molecolare, Merck Research Laboratories, 00040 Rome, Italy. barbara_cipriani@merck.com
Barbara
B
Cipriani
Arthur
A
Fridman
Claus
C
Bendtsen
Shridar
S
Dharmapuri
Carmela
C
Mennuni
Irene
I
Pak
Giuseppe
G
Mesiti
Guido
G
Forni
Paolo
P
Monaci
Ansu
A
Bagchi
Gennaro
G
Ciliberto
Nicola
N
La Monica
Elisa
E
Scarselli
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008321:Mammary Glands, Animal / Q000000981:diagnostic imaging; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D011237:Predictive Value of Tests; D051381:Rats; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016896:Treatment Outcome; D014463:Ultrasonography; D014611:Vaccination
D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D007371:Interferon-gamma