allogeneic bone marrow chimeras Successful therapy of metastatic cancer using tumor vaccines in mixed

Abstract A frequent outcome of allogeneic stem cell transplantation (alloSCT) in the treatment of leukemia is the destruction of the host hematolymphoid compartment, and thus the malignancy, through the combined action of high dose chemoradiotherapy and a T cell-mediated graft-versus host-effect. Unfortunately, alloSCT is frequently limited by toxicity, including graft-versus-host disease (GVHD), and has not been successful in the treatment of tumors derived from solid organs. Here we report a novel cooperation between host and donor T cells in the response to a tumor cell vaccine given after a non-myeloablative allogeneic stem cell transplantation (NST) protocol that achieves stable mixed bone marrow chimerism. Treatment of animals with NST, posttransplant donor -lymphocyte infusions (DLI), and a vaccine, comprising irradiated autologous tumor cells mixed with a GMCSF producing bystander line, results in potent and specific anti- -tumor immunity. This combined modality immunotherapy, administered after surgical removal of the primary tumor, cured metastatic mammary cancer in the majority of animals without inducing GVHD. Cured animals contained tumorspecific T cells of both host -and donor origin, but immunodeficient hosts could not be cured by NST, DLI, and vaccine administration. Thus, transfer of allogeneic donor T cells may help break functional tolerance of a host immune system to a solid tumor, thereby providing a rationale for the generation of mixed hematopoietic chimerism by NST prior to tumor cell vaccination. Corresponding author: Ephraim J. Fuchs, M.D. E-mail: fuchsep@jhmi.edu From bloodjournal.hematologylibrary.org by guest on June 7, 2013. For personal use only.