| Abstract: |
Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating (α-galactosylceramide (α-GalCer) that targets the immune adjuvant properties of NKT cells. In the Eμ-myc transgenic mouse model, single therapeutic vaccination of irradiated, (α-GalCer-loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine-induced antilymphoma immunity required NKT cells, NK cells, and CD8 T cells, and early IL-12-dependent production of IFN-γ. CD4 T cells, gamma/delta T cells, and IL-18 were not critical. Vaccine treatment induced a large systemic spike of IFN-(γ and transient peripheral expansion of both NKT cells and NK cells, the major sources of IFN-γ. Furthermore, this vaccine approach was assessed in several other hematopoietic tumor models and was also therapeutically effective against AMLETO9a acute myeloid leukemia. Replacing (α-GalCer with β-mannosylceramide resulted in prolonged protection against Eμ-myc lymphoma. Overall, our results demonstrate a potent immune adjuvant effect of NKT cell ligands in therapeutic anticancer vaccination against oncogenedriven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies. © 2012 by The American Society of Hematology. |
| Keywords: |
controlled study; acute granulocytic leukemia; drug efficacy; nonhuman; flow cytometry; cd8+ t lymphocyte; mouse; animals; mice; mice, knockout; animal experiment; animal model; antineoplastic activity; mice, inbred c57bl; transgenic mouse; mice, transgenic; b cell lymphoma; lymphoma, b-cell; immunotherapy; gamma interferon; cancer vaccines; genes, myc; cd4+ t lymphocyte; vaccination; natural killer cell; killer cells, natural; tumor immunity; cytokine production; cytotoxicity, immunologic; immunological adjuvant; interferon-gamma; tumor vaccine; adjuvants, immunologic; cell expansion; interleukin 12; oncogene myc; alpha galactosylceramide; interleukin 18; natural killer t-cells; interleukin-12; gamma delta t lymphocyte; interleukin-18; galactosylceramides; genes, t-cell receptor delta
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