The disialoganglioside, GD3, is expressed by the leukemia cell membranes of the majority of patients with T-cell acute lymphoblastic leukemia (ALL). This situation is distinctly different for non-T-cell (B-cell precursor) ALL wherein, no increase in GD3 is observed, suggesting that, within the context of childhood ALL, this ganglioside appears to be a tumor-associated antigen, specific for lymphoblasts of T-cell origin. In addition to confirming the quantitative differences in GD3 content of isolated glycolipid fractions of leukemia cell membrane within immunological subclasses of this disease, the use of a murine IgG3 monoclonal anti-GD3 antibody (R24) has demonstrated that this novel ganglioside antigen on T- cell leukemic lymphoblasts serves as a relevant target antigen for antibody mediated cytolysis in vitro. Further more, reactivity of T-cell leukemic lymphoblast with the monoclonal antibody, R24 may be associated with longer remission duration. The major objective of this proposal is to evaluate in a Phase I setting the maximum tolerated in children with T-cell lymphoid malignancy refractory to conventional therapy. In addition, we will prospectively assess the prognostic significance of GD3 expression by T- cell leukemic lymphoblasts as well as serum GD3 levels, reflecting shed ganglioside, in concert with other clinical variables, within a population of T-cell ALL patients entered on treatment protocols of the Childrens Cancer Study Group. In addition, co-expression of GD3 with other antigenic determinants by T-cell lymphoblasts, specifically CD3, will be evaluated utilizing two-color immunofluorescence. The role of GD3 in both effector and lytic cells utilizing anti-GD3 as a potentiating and/or blocking agent in a number of in vitro cytotoxicity assays will be evaluating to further define the mechanism(s) involved in antibody-mediated cell killing. Finally, laboratory investigations of upregulation of GD3 expression (biosynthesis) by differentiating agents and/or lymphokines will be undertaken to potentiate the cytotoxic utility of the R24 monoclonal antibody as a basis for further clinical trials of R24 in combination with additional biological agents in T-cell ALL.
| Merritt, W D; Der-Minassian, V; Reaman, G H (1994) Increased GD3 ganglioside in plasma of children with T-cell acute lymphoblastic leukemia. Leukemia 8:816-22 |
