) Development of novel therapeutic approaches will be essential to improve the therapeutic index and outcome of children and adults with ALL. The hypothesis of Project 6 is that interactions between host cells and tumor cells result in a survival advantage for the tumor. Here, we propose to develop strategies to modulate these interactions to either directly lyse the tumor cell or alter its survival advantage. Two approaches based upon our preliminary data are proposed. First, we will attempt to induce T cell mediated anti-ALL specific immunity. Second, we will attempt to modulate de novo angiogenesis thereby altering the survival of the ALL cell within its microenvironment. Extensive preliminary evidence in both of these areas are in hand which suggest that these objectives can be achieved. Therefore, two Specific Aims are proposed: 1) To undertake clinical trials using vaccination and/or adoptive therapy to induce or augment autologous T-cell mediated anti-ALL specific immunity to determine feasibility, safety, and clinical outcome; and 2) To develop pre-clinical strategies to modulate angiogenesis within the bone marrow of patients with ALL with the view to undertake clinical trials. The success of these aims requires: 1) identification of patients who are appropriate for experimental therapy at relapse and prior to relapse as defined by collaborations with Projects 8 and 9; and 6) identification of specific intervals of time extending from diagnosis, on treatment, off treatment, or at the time of relapse when the proposed manipulations between host cells and tumor cells will be optimal for intervention. To achieve these goals, we propose to develop and validate in vitro and in vivo assays that quantify tumor immunity and de novo angiogenesis with the view to define """"""""windows of therapeutic opportunity"""""""" and provide surrogate markers of outcome. Armed with these biologic endpoints, we will first conduct Phase I and II clinical trials in years 1 to 3 and then in later years attempt to integrate these strategies into Project 4.
Showing the most recent 10 out of 214 publications
