Acute exercise as a strategy to improve the safety and efficacy of donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation

Abstract

Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is one of the main treatments for hematological malignancies. HCT provides prolonged disease-free survival for many patients, but relapse remains the most frequent cause of death. Donor lymphocytes infusion (DLI) is used after HCT to treat or prevent disease relapse by boosting the graft versus tumor (GvT) effect, however it increases the risk of graft versus host disease (GvHD), the most frequent HCT-associated complication. DLI can be modified for reduce the toxicity and enhance its activity. Exercise induces the mobilization of certain leukocytes subtypes into the peripheral circulation specially those presenting greater cytotoxicity, antigen experience, and tissue migration potential (eg. NK cells, ³´ T cells). Performing DLI with blood collected after an exercise session may increase its efficacy and reduce toxicity. Hypothesis: Our hypothesis therefore is that the GvHD risk will be lower when donor lymphocytes are collected post-exercise, without decreasing but in fact improving its GvT effect. Aim: Identify whether exercise can improve the safety and efficacy of donor lymphocyte infusions (DLI) after HCT in a leukemia model. Can the GVL effect of DLI following exercise be enhanced in vivo by cytokines without inducing GvHD? Methods: Bone marrow will be collected from healthy volunteers for transplantation to transgenic NSG-Tg (Hu-IL15) mice. Autologous leukemia will be induced using a mixed lineage leukemia (MLL) fusion gene in human CD34+ stem cells and allogeneic leukemia using a luciferase tagged K562 cell line. Lymphocytes will be collected from the same donors before and immediately after an acute bout of aerobic exercise and transplanted to the tumor bearing NSG-Tg mice Endpoints include tumor growth, survival, percentage human chimerism, and xeno-GvHD, as well as identifying the cell types (NK-cells, CD4+ and CD8+ TCR-±² T-cells, TCR-³´ T-cells) responsible for the exercise effects.