The therapeutic efficacy of murine anti-tumor T cells: freshly isolated T cells are more therapeutic than T cells expanded in vitro.
Adoptive immunotherapy (AIT) involving transfer of tumor-sensitized T lymphocytes in combination with cyclophosphamide (CY)-injection results in the eradication of the C57BL/6J (B6) rhabdomyosarcoma, 76-9 and is associated with the accumulation of a large number of tumor-infiltrating lymphocytes (TIL). Using immune spleen cells (ISC) from B6 and congenic B6. PL. Thy-1a mice, it was shown that most (> or = 97%) of the TIL were donor-derived. This in situ increase in donor-derived T cells was confirmed by using positively-selected Thy- 1.1+ and Thy- 1.2+ TIL for AIT after isolating them from regressing tumors and expanding them in rIL-2. The extent of CD8+ TIL expansion in vivo correlated with the numbers of TIL adoptively transferred and this in turn determined the degree of anti-tumor effects. It was evident, however, that these in vitro-expanded TIL expressing mRNA for TNF alpha and IFN gamma were qualitatively different and therapeutically less efficacious than the T cells associated with ISC or with freshly-isolated TIL. Unlike freshly isolated TIL that expressed specific cytotoxicity towards the 76-9 targets in vitro, IL-2 expanded TIL killed 76-9 cells and unrelated tumor targets to the same extent. A cytotoxic CD8+ T cell line derived from ISC and selected for activity against the 76-9 tumor cells showed no therapeutic efficacy. The data suggest that, in this tumor model, expansion of CD8+ T cells in vitro selects against anti-tumor efficacy.
Evans
R
R
Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Kamdar
S J
SJ
Duffy
T M
TM
Krupke
D M
DM
Fuller
J A
JA
Dudley
M E
ME
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002469:Cell Separation; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D016219:Immunotherapy, Adoptive; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D051379:Mice; D008810:Mice, Inbred C57BL; D012074:Remission Induction; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*; D018800:Thy-1 Antigens / Q000032:analysis
D018800:Thy-1 Antigens; D003520:Cyclophosphamide