A Th1-inducing adenoviral vaccine for boosting adoptively transferred T cells.
Although the benefits of adoptive T-cell therapy can be increased by prior lymphodepletion of the recipient, this process usually requires chemotherapy or radiation. Vaccination with antigens to which the transferred T cells respond should be a less toxic means of enhancing their activity, but to date such vaccines have not been effective. We, therefore, determined which characteristics an adenoviral vaccine has to fulfill to optimally activate and expand adoptively transferred antigen-specific T cells in vivo. We evaluated (i) antigen, (ii) flagellin, a Toll-like receptor (TLR) 5 ligand, and (iii) an inhibitor of the antigen-presenting attenuator A20. Vaccination of mice before T-cell transfer with a vaccine that contained all three components dramatically enhanced the effector function of ovalbumin (OVA)-specific T cells as judged by the regression of established B16-OVA tumors compared to one- and two-component vaccines. Immunization with the three-component vaccine induced a strong Th1 environment, which was critical for the observed synergy and proved as effective as cytoxan-induced lymphodepletion in enhancing in vivo T-cell expansion. Thus, the combination of our vaccine with T-cell therapy has the potential to enhance and broaden adoptive cellular immunotherapy.
Song
Xiao-Tong
XT
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, Texas 77030, USA. xsong1@bcm.edu
Turnis
Meghan E
ME
Zhou
Xiaoou
X
Zhu
Wei
W
Hong
Bang-Xing
BX
Rollins
Lisa
L
Rabinovich
Brian
B
Chen
Si-Yi
SY
Rooney
Cliona M
CM
Gottschalk
Stephen
S
D000256:Adenoviridae / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005408:Flagellin / Q000235:genetics; D007117:Immunization, Secondary / Q000379:methods; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000378:metabolism; D014765:Viral Vaccines / Q000276:immunology*
D000941:Antigens; D019496:Cancer Vaccines; D034741:RNA, Small Interfering; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D005408:Flagellin; D010047:Ovalbumin