Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras.
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 nonmyeloablative allogeneic stem cell transplantation (NST) protocol that achieves stable mixed bone marrow chimerism. Treatment of animals with NST, posttransplantation donor lymphocyte infusions (DLIs), and a vaccine, comprising irradiated autologous tumor cells mixed with a granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing bystander line, results in potent and specific antitumor immunity. This combined modality immunotherapy, administered after surgical removal of the primary tumor, cured metastatic mammary cancer in most animals without inducing GVHD. Cured animals contained tumor-specific 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.
Luznik
Leo
L
Divisions of Hematopoiesis/Immunology and Hematologic Malignancies, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Slansky
Jill E
JE
Jalla
Sanju
S
Borrello
Ivan
I
Levitsky
Hyam I
HI
Pardoll
Drew M
DM
Fuchs
Ephraim J
EJ
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001854:Bone Marrow Cells; D019496:Cancer Vaccines / Q000276:immunology; D006086:Graft vs Host Disease; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D018380:Hematopoietic Stem Cell Transplantation; D007167:Immunotherapy; D007959:Lymphocyte Culture Test, Mixed; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000601:surgery / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor