Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors.
Ex vivo-expanded tumor-infiltrating lymphocytes infused into lymphodepleted recipients has clear antitumor efficacy. More practical sources of such antitumor lymphocytes would broaden the application of this approach. Previously, we described an in situ vaccination combining chemotherapy with intratumoral injection of CpG-enriched oligonucleotides, which induced T-cell immunity against established lymphoma. An ongoing clinical trial of this maneuver has demonstrated clinical responses in lymphoma patients. Here, we use this vaccine maneuver to generate immune cells for transfer into irradiated, syngeneic recipients. Transferred tumor-specific T-effector (T(eff)) cells preferentially expanded, increasing the T(eff)/T-regulatory (T(reg)) ratio in these "immunotransplantation" recipients and curing large and metastatic tumors. Donor T cells were necessary for tumor protection, and CD8 T-cell immune responses were enhanced by posttransplantation booster vaccination. Hematopoietic stem cell transplantation is a standard therapy for lymphoma. Therefore, in situ tumor vaccination followed by immunotransplantation of harvested tumor-specific T cells could be directly tested in clinical trials to treat otherwise resistant malignancies.
Brody
Joshua D
JD
Division of Oncology, Department of Medicine, Stanford University Medical Center, CA.
Goldstein
Matthew J
MJ
Czerwinski
Debra K
DK
Levy
Ronald
R
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000276:immunology / Q000494:pharmacology; D007117:Immunization, Secondary; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015552:Injections, Intralesional; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides; D012720:Severity of Illness Index; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D019444:Vaccines, DNA / Q000494:pharmacology*
D019496:Cancer Vaccines; C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; D019444:Vaccines, DNA; D004247:DNA