Nonmyeloablative chemotherapy followed by T-cell adoptive transfer and dendritic cell-based vaccination results in rejection of established melanoma.
We demonstrated previously that dendritic cell (DC)-based vaccines could mediate a specific and long-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 200 mg/kg cyclophosphamide (Cy) and 100 mg/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.
Koike
Nobusada
N
Department of Translational Science, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Pilon-Thomas
Shari
S
Mulé
James J
JJ
D019264:Adoptive Transfer; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects / Q000528:radiation effects; D007371:Interferon-gamma / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D014916:Whole-Body Irradiation
D019496:Cancer Vaccines; D007371:Interferon-gamma; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine