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

Leo Luznik, Jill E. Slansky, Sanju Jalla, Ivan M Borrello, Hyam I. Levitsky, Andrew Mark Pardoll, Ephraim J Fuchs

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)1645-1652
Number of pages8
JournalBlood
Volume101
Issue number4
DOIs
StatePublished - Feb 15 2003

Fingerprint

Cancer Vaccines
Tumors
Bone
Bone Marrow
T-cells
Stem Cell Transplantation
Stem cells
Neoplasms
Grafts
T-Lymphocytes
Chimerism
Animals
Vaccines
Lymphocytes
Cells
Graft vs Host Disease
Therapeutics
Chemoradiotherapy
Immune system
Granulocyte-Macrophage Colony-Stimulating Factor

ASJC Scopus subject areas

  • Hematology

Cite this

Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras. / Luznik, Leo; Slansky, Jill E.; Jalla, Sanju; Borrello, Ivan M; Levitsky, Hyam I.; Pardoll, Andrew Mark; Fuchs, Ephraim J.

In: Blood, Vol. 101, No. 4, 15.02.2003, p. 1645-1652.

Research output: Contribution to journalArticle

@article{4bad1d6530e541abb4392f31c23e0b4b,
title = "Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras",
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 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.",
author = "Leo Luznik and Slansky, {Jill E.} and Sanju Jalla and Borrello, {Ivan M} and Levitsky, {Hyam I.} and Pardoll, {Andrew Mark} and Fuchs, {Ephraim J}",
year = "2003",
month = "2",
day = "15",
doi = "10.1182/blood-2002-07-2233",
language = "English (US)",
volume = "101",
pages = "1645--1652",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

TY - JOUR

T1 - Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras

AU - Luznik, Leo

AU - Slansky, Jill E.

AU - Jalla, Sanju

AU - Borrello, Ivan M

AU - Levitsky, Hyam I.

AU - Pardoll, Andrew Mark

AU - Fuchs, Ephraim J

PY - 2003/2/15

Y1 - 2003/2/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037441898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037441898&partnerID=8YFLogxK

U2 - 10.1182/blood-2002-07-2233

DO - 10.1182/blood-2002-07-2233

M3 - Article

C2 - 12406877

AN - SCOPUS:0037441898

VL - 101

SP - 1645

EP - 1652

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -