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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2233.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1645-1652
TRANSPLANTATION
Successful therapy of metastatic cancer using tumor
vaccines in mixed allogeneic bone marrow chimeras
Leo Luznik,
Jill E. Slansky,
Sanju Jalla,
Ivan Borrello,
Hyam I. Levitsky,
Drew M. Pardoll, and
Ephraim J. Fuchs
From the Divisions of Hematopoiesis/Immunology and
Hematologic Malignancies, Sidney Kimmel Cancer Center at Johns Hopkins,
Baltimore, MD.
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.
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