Anti-3rd party human ctl's generated from autologous or allogeneic t cells are endowed with potent gvl activity in the absence of gvho

The establishment of donor type cell lines or clones capable of killing leukemia o:lls in the absence of alloreactivity against host cells, represent a most desirable goal in BMT. Recently, it has been shown that anti-3rd party CTLs depleted of alloreactivity by me ins of IL-2 deprivation are endowed with marked veto activity and therefore might potentially facilitate bone marrow allografting without graft versus host disease (GVHD). The veto mechanism is still obscure. Recent evidence indicates that the veto activity of murine a iti3rd party CTLs is dependent upon the simultaneous expression of both CDS and FasL. In the present study we demonstrate in a human/mouse radiation chimera, which allows the growth of human cells from patients with acute and chronic leukemia; that human n Dnalloreactive anti-third party CTLs are endowed with a potent Graft Vs Leukemia (GVL) activity against B-CLL. In two experiments, infusion of non-alloreactive CTLs from an HLA disparate allogeneic donor led to 92.7 and 93.7 percent eradication of leukemic ce Ils. In two additional experiments, lower but still high levels of leukemia eradication (60.1% and 75%) were found with ami 3rd party CTLs generated using autologous T cells fiom the patients. In vitro study using transwell plates showed that cell contact is required for the killing of leukemic cells. Preliminary studies aimed at testing the GVL activitj of allogeneic non-alloreactive CTLs against fresh T-ALL cells of a patient in the hurr an/ mouse chimera, exhibited a marked eradication (87.47%) of leukemic cells similar to hat attained against B-CLL. In contrast, no GVL could be detected against AML ce Ils. Altogether our results suggest a rational for the treatment of B-CLL patients with anti- 3rd party CTLs either in the context of autologous or allogeneic BMT. In addition, considei ing the reported lack of GVL activity against ALL cells by NK cells or donor lymphoc yte infusions, our preliminary results against T-ALL leukemia are encouraging. Furl 1er experiments comparing fresh AML and ALL ceils for their sensitivity to non-alloreac ive CTLs are in progress.