THE ROLE OF B7 COSTIMULATION BY MURINE ACUTE MYELOID-LEUKEMIA IN THE GENERATION AND FUNCTION OF A CD8(-CELL LINE WITH POTENT IN-VIVO GRAFT-VERSUS-LEUKEMIA PROPERTIES() T)

Relapse is more frequent after autologous than allogeneic bone marrow transplantation (BMT), due in part to lack of T-lymphocyte mediated al logeneic graft-versus-leukemia (GVL) effects. Infusions of leukemia-re active T cells to patients after autologous BMT may be a means for pro viding a GVL effect. Costimulation of T cells by binding of the CD28 r eceptor on T cells with B7-counter receptors on antigen presenting cel ls amplifies antigen-specific T-cell responses, To enhance generation of leukemia reactive cytotoxic T lymphocytes (CTL), the murine B7-1- a nd B7-2-costimulatory molecule cDNAs were introduced into the MHC clas s I+, class II-, murine meyloid leukemia cell line C1498. B7-1 express ion greatly enhanced the ability of the leukemia cells to generate and expand leukemia reactive CTL in vitro. A highly cytolytic and C1498 s pecific CD8(+) CTL line was generated by B7-1 costimulation. This CTL line proliferated autonomously and produced interleukin-2 when provide d B7-1 or B7-2 costimulation by C1498 leukemia cells. To test the in v ivo antileukemia properties of this CTL line, irradiated syngeneic BMT recipients were given graded doses of leukemia cells on day 0, follow ed by CTL infusions beginning on day 1 post-BMT. Recipients of 10(7) C TL had a 3 log reduction in leukemia burden such that 100% of mice wer e protected from a supralethal leukemic cell dose. Sustained immune re sponses were detectable up to 3 months postinfusion of the CTL line. B 7-1 or B7-2 costimulation in vivo did not augment antileukemia effects of infused CTL post BMT. These results suggest that B7 costimulation of leukemia reactive CTL may be important for their ex vivo generation and expansion for use in human adoptive immunotherapy of leukemia. (C ) 1997 by The American Society of Hematology.