CD8+ T cells activated during the course of murine acute myelogenous leukemia elicit therapeutic responses to late B7 vaccines after cytoreductive treatment.
We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice can be cured with a B7 vaccine if immunized early in the disease and that CD8+ T cells are necessary for tumor rejection. However, when B7 vaccine is administered 2 weeks after leukemia inoculation, the effect is only prolonged survival, ending in death virtually of all the mice. To distinguish between tumor kinetics and tumor-induced immunosuppression as potential mechanisms eliminating the therapeutic potential of late B7 vaccines, we performed in vitro T-cell studies during leukemia progression and in vivo studies on the clinical outcome of late B7 vaccines in combination with prior cytoreductive chemotherapy. Our results show that CD8+ T cells from leukemic mice 1 and 2 weeks after leukemia inoculation proliferate more vigorously in response to in vitro activation than cells from normal mice and produce Th1-type cytokines interleukin-2 and interferon-gamma. Cytotoxic T lymphocyte (CTL) assays demonstrate that cells from week-2 vaccinated mice (which succumb to their leukemia), surprisingly develop a stronger CTL activity than cells from week-1 vaccinated mice (which reject their leukemia). Finally, the combination of late chemotherapy and late B7 vaccine administration can cure only 20% of leukemic mice, whereas early chemotherapy and the same late B7 vaccine administration cure 100% of leukemic mice. These results demonstrate that in murine AML tumor growth does not induce T-cell anergy or a Th2 cytokine profile and suggest that tumor growth is most likely to be the limiting factor in the curative potential of late B7 vaccines.
Dunussi-Joannopoulos
K
K
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Krenger
W
W
Weinstein
H J
HJ
Ferrara
J L
JL
Croop
J M
JM
D000208:Acute Disease; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000627:therapeutic use; D005069:Evaluation Studies as Topic; D005260:Female; D007115:Immunization Schedule; D016233:Immunotherapy, Active; D016219:Immunotherapy, Adoptive; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007953:Leukemia, Radiation-Induced / Q000473:pathology; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014612:Vaccines / Q000276:immunology*
D000964:Antimetabolites, Antineoplastic; D018122:B7-1 Antigen; D008222:Lymphokines; D014612:Vaccines; D003561:Cytarabine