Vaccination regimens incorporating CpG-containing oligodeoxynucleotides and IL-2 generate antigen-specific antitumor immunity from T-cell populations undergoing homeostatic peripheral expansion after BMT.
Development of CD8(+) T-cell responses targeting tumor-associated antigens after autologous stem cell transplantations (ASCTs) might eradicate residual tumor cells and decrease relapse rates. Because thymic function dramatically decreases with aging, T-cell reconstitution in the first year after ASCT in middle-aged patients occurs primarily by homeostatic peripheral expansion (HPE) of mature T cells. To study antigen-specific T-cell responses during HPE, we performed syngeneic bone marrow transplantations (BMTs) on thymectomized mice and then vaccinated the mice with peptides plus CpG-containing oligodeoxynucleotides (CpGs) in incomplete Freund adjuvant and treated the mice with systemic interleukin-2 (IL-2). When CD8(+) T-cell responses were measured ex vivo, up to 9.1% of CD8(+) T cells were specific for tumor-associated epitopes. These large T-cell responses were generated by synergism between CpG and IL-2. When we injected mice subcutaneously with tumor cells 14 days after BMT and then treated them with peptide + CpG-containing vaccines plus systemic IL-2, survival was increased and tumor growth was inhibited in an epitope-specific manner. Depletion of CD8(+) T cells eliminated epitope-specific antitumor immunity. This is the first report to demonstrate that CD8(+) T-cell responses capable of executing antitumor immunity can be elicited by CpG-containing vaccines during HPE.
Kochenderfer
James N
JN
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. kochendj@mail.nih.gov
Simpson
Jessica L
JL
Chien
Christopher D
CD
Gress
Ronald E
RE
D000818:Animals; D000951:Antigens, Neoplasm / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation; D018899:CpG Islands; D007109:Immunity; D007376:Interleukin-2 / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides