Efficacy of GM-CSF-producing tumor vaccine after docetaxel chemotherapy in mice bearing established Lewis lung carcinoma.
In this report, we evaluated the efficacy of a GM-CSF-producing tumor vaccine given before and after docetaxel in mice bearing established lung tumors. Mice bearing established 3LL tumors were treated with docetaxel and tumor vaccines transduced with either control or GM-CSF adenoviral vectors. Docetaxel (5-20 mg/kg) treatment alone had only a minimal effect on growth of established 3LL tumors in vivo, although docetaxel was cytotoxic to 3LL cells in vitro. When mice bearing established 3LL tumors were pretreated with docetaxel followed by vaccination with irradiated GM-CSF- transduced 3LL tumor cells, significant tumor regression and prolonged survival were observed compared with chemotherapy alone. Delaying docetaxel treatment until after tumor vaccination abrogated the vaccine's anti-tumor effects. Mice that survived treatment were able to resist a lethal rechallenge of 3LL tumor cells. Memory CTL specific for an epitope (MUT-1) derived from 3LL were detected in surviving mice. Docetaxel induced a mild lymphodepletion in mice, both CD4 and CD8 subsets were reduced in LN and spleens. Interestingly, docetaxel also diminished the number of memory CD8+ T cells (CD122+) and possible CD4+ CD25+ Foxp3+ natural Treg cells. Docetaxel treatment did not affect antigen-driven proliferation of naive T cells but significantly promoted survival of activated T cells. Thus, augmentation of vaccine induced antitumor immunity in docetaxel-treated mice primarily due to the enhanced survival of antigen-experienced T cells.
Chu
Yiwei
Y
Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA.
Wang
Li-Xin
LX
Yang
Guojun
G
Ross
Helen J
HJ
Urba
Walter J
WJ
Prell
Rodney
R
Jooss
Karin
K
Xiong
Sidong
S
Hu
Hong-Ming
HM
D000256:Adenoviridae; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000378:metabolism / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D002470:Cell Survival; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D043823:Taxoids / Q000627:therapeutic use*; D014614:Vaccines, Synthetic / Q000627:therapeutic use
D019496:Cancer Vaccines; D043823:Taxoids; D014614:Vaccines, Synthetic; D000077143:Docetaxel; D016178:Granulocyte-Macrophage Colony-Stimulating Factor