This application addresses broad challenge area (10) Information Technology for Processing Health Care Data for Research"""""""" and specific challenge topic 10-CA-102 Predictive Mathematical Models of Normal and Cancer Processes. This proposal will develop mathematical models to study the impact of three FDA approved drugs for interactions with donor lymphocyte infusion in a murine model of MHC-matched allogeneic transplantation that employs novel acute leukemia models driven by the human bcr-abl mutation. The long range goal of this research is to develop mathematical methods that can guide rational design of multimodality therapies for control of residual leukemia present after allogeneic transplantation. Relapse of acute leukemia is the most common cause of treatment failure after allogeneic transplantation. Unlike some hematological malignancies such as chronic myelogenous leukemia, relapse of acute leukemia after transplant is not effectively treated with allogeneic donor lymphocyte infusion or other immune therapies. The mechanism of this failure is not yet fully elucidated. The results of these prior mechanistic studies suggest the hypothesis that the relative kinetics of leukemia cell and allogeneic T cell proliferation rather than intrinsic deficiency in immunity is the major mechanism for the lack of efficacy of donor lymphocyte infusion in acute leukemia. Quantitative modeling of the kinetics of leukemia and T cell population dynamics in vivo is a necessary first step in the rational combination of existing immunological and pharmacological therapies that will substantially increase the probability of control of residual ALL.
Aim 1 : Construct a differential equation based model to mechanistically describe leukemia and alloreactive T cell population kinetics in vivo following allogeneic donor lymphocyte infusion. Parameters will be derived from in vitro experiments and then verified in vivo. Simulations will then be performed to predict the potential outcomes of the interventions proposed in Aim 2, as well as to design the experimental sampling frequencies needed for statistical analysis.
Aim 2 : To test the hypothesis that mathematical model directed administration of currently available drugs can substantially improve the efficacy of allogeneic donor lymphocyte infusion in controlling residual acute lymphoblastic leukemia. We will test three FDA approved drugs with different mechanisms of action: (a) imatinib (a tyrosine kinase inhibitor of the bcr-abl fusion protein);(b) pulsatile methotrexate (an antimetabolite);and (c) anti-CD20 monoclonal antibody. If these studies demonstrate that immune control of residual acute leukemia can be enhanced by such maneuvers, rapid translation of the mechanistic insights into clinical trials is envisioned. Public Health Relevance Many patients with leukemia, a blood cancer, die because the leukemia comes back even after intensive treatment with bone marrow transplantation. This project will develop mathematical techniques that will help doctors combine chemotherapy and immunological therapy in new ways that will keep leukemia from coming back after bone marrow transplantation.
Many patients with leukemia, a blood cancer, die because the leukemia comes back even after intensive treatment with bone marrow transplantation. This project will develop mathematical techniques that will help doctors combine chemotherapy and immunological therapy in new ways that will keep leukemia from coming back after bone marrow transplantation.
