NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma

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-galact...

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Bibliographic Details
Published in:Blood Vol. 120; no. 15; p. 3019
Main Authors: Mattarollo, Stephen R, West, Alison C, Steegh, Kim, Duret, Helene, Paget, Christophe, Martin, Ben, Matthews, Geoffrey M, Shortt, Jake, Chesi, Marta, Bergsagel, P Leif, Bots, Michael, Zuber, Johannes, Lowe, Scott W, Johnstone, Ricky W, Smyth, Mark J
Format: Journal Article
Language:English
Published: United States 11.10.2012
Subjects:
Adjuvants, Immunologic - administration & dosage
Animals
Cancer Vaccines - therapeutic use
Cytotoxicity, Immunologic - immunology
Female
Flow Cytometry
Galactosylceramides - administration & dosage
Genes, myc - genetics
Genes, T-Cell Receptor delta - physiology
Humans
Immunotherapy
Interferon-gamma - metabolism
Interleukin-12 - physiology
Interleukin-18 - physiology
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Killer Cells, Natural - pathology
Lymphoma, B-Cell - immunology
Lymphoma, B-Cell - metabolism
Lymphoma, B-Cell - prevention & control
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Natural Killer T-Cells - immunology
Natural Killer T-Cells - metabolism
Natural Killer T-Cells - pathology
Vaccination
ISSN:1528-0020, 1528-0020
Online Access:Get more information
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Summary: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 AML-ETO9a 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 oncogene-driven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2012-04-426643