A CpG-loaded tumor cell vaccine induces antitumor CD4+ T cells that are effective in adoptive therapy for large and established tumors.
We designed a whole tumor cell vaccine by "loading" lymphoma tumor cells with CG-enriched oligodeoxynucleotide (CpG), a ligand for the Toll-like receptor 9 (TLR9). CpG-loaded tumor cells were phagocytosed, delivering both tumor antigen(s) and the immunostimulatory CpG molecule to antigen-presenting cells (APCs). These APCs then expressed increased levels of costimulatory molecules and induced T-cell immunity. TLR9 was required in the APCs but not in the CpG-loaded tumor cell. We demonstrate that T cells induced by this vaccine are effective in adoptive cellular therapy for lymphoma. T cells from vaccinated mice transferred into irradiated, syngeneic recipients protected against subsequent lymphoma challenge and, remarkably, led to regression of large and established tumors. This therapeutic effect could be transferred by CD4(+) but not by CD8(+) T cells. A CpG-loaded whole-cell vaccination is practical and has strong potential for translation to the clinical setting. It is currently being tested in a clinical trial of adoptive immunotherapy for mantle-cell lymphoma.
Goldstein
Matthew J
MJ
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Varghese
Bindu
B
Brody
Joshua D
JD
Rajapaksa
Ranjani
R
Kohrt
Holbrook
H
Czerwinski
Debra K
DK
Levy
Shoshana
S
Levy
Ronald
R
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018899:CpG Islands / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D014611:Vaccination
D019496:Cancer Vaccines