Optimized systemic dosing with CpG DNA enhances dendritic cell-mediated rejection of a poorly immunogenic mammary tumor in BALB/c mice.
To model a clinical trial of dendritic cell (DC) therapy of a poorly immunogenic mammary tumor, we treated BALB/c mice bearing an established TS/A mammary tumor with lysate-pulsed DCs and CpG DNA. We observed that the dose of CpG DNA required to activate DCs in vitro was insufficient to mediate tumor rejection in vivo. We therefore undertook in vivo studies to identify an optimized dose of CpG DNA for tumor therapy, defined as the lowest and least frequently administered dose of CpG DNA that mediated complete tumor rejection. We show that one priming dose of 15 nanomoles and one booster dose of 10 nanomoles of CpG DNA given 7 days apart, respectively, with lysate-loaded DCs were sufficient to mediate complete tumor rejection in vivo. This dose of CpG DNA was 42-fold higher than that required to activate DCs in vitro but was not associated with any toxicity in mice. Also, the cured mice rejected a subsequent challenge with fresh TS/A tumor, and both CD4(+) and CD8(+) T cells were required for tumor rejection. We conclude that effective DC-based therapy of a poorly immunogenic TS/A tumor is enhanced by optimized dosing of CpG DNA. Our data have important implications for DC-based clinical trials of breast cancer immunotherapy.
Cai
Quan
Q
Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Kublo
Lyubov
L
Cumberland
Rachel
R
Gooding
William
W
Baar
Joseph
J
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D015226:Dinucleoside Phosphates / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis
D016207:Cytokines; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide