Journal
JOURNAL OF IMMUNOTHERAPY
Volume 31, Issue 4, Pages 402-412Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e31816cabbb
Keywords
dendritic cells; immunotherapy; lymphopenia
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Funding
- NCI NIH HHS [R01 CA071669, R01-CA-071669-09] Funding Source: Medline
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We demonstrated previously that dendritic cell (DC)-based vaccines could mediate a specific and Icing-lasting antitumor immune response during early lymphoid reconstitution after lethal irradiation and bone marrow transplant. The purpose of this current study was to examine the potential therapeutic efficacy of DC-based vaccines in combination with sublethal lymphodepletion and T-cell transfer. In an aggressive model of melanoma, treatment with the combination of 200mg/kg cyclophosphamide (Cy) and 100mg/kg fludarabine (Flu) led to a lymphopenic state lasting approximately 14 days, but had no effect on the growth of an established M05 melanoma. Addition of ovalbumin (OVA) peptide-pulsed DC-based immunization resulted in a delay in tumor growth but did not enhance overall survival in this model. To improve treatment, adoptively transferred naive T cells were added. After induction of lymphopenia with Cy and Flu, transferred T cells demonstrated an activated memory phenotype including high expression of CD44 and low expression of CD62L. Induction of lymphopenia with Cy and Flu in combination with adoptive transfer of naive T cells and OVA peptide-pulsed DCs immunization led to an enhancement in the number of OVA specific, CD8(+) T cells that demonstrated specific cytotoxic activity, proliferation, and interferon-gamma production in response to the OVA expressing M05 melanoma. This combination therapy also led to tumor regression and enhanced survival in mice bearing M05 melanoma.
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