Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing tumor vaccines

Abstract

For many cancers, autologous bone marrow transplantation (BMT) achieves a minimal residual disease state, yet relapse rates remain high. Using a syngeneic murine bone marrow transplant model, we demonstrate that vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing autologous tumor cells is effective in the post-BMT period and actually results in a greater tumor-free survival than vaccination in the nontransplant setting. Employing T cells specific for a model tumor-antigen, we find that transplantation of the tumor-bearing host results in a massive expansion and activation of tumor-specific T cells in the early posttransplant period, but this response rapidly declines in association with tumor progression. Immunization with irradiated GM-CSF tumor cells during the period of immune reconstitution results in the sustained amplification and activation of this response that closely correlates with freedom from relapse. These results demonstrate the feasibility of integrating GM-CSF vaccines in the postautologous BMT setting and suggest mechanisms that may contribute to the observed efficacy of immunization during the critical period of immune reconstitution.

Adjuvant therapeutic vaccination in patients with non-small cell lung cancer made lymphopenic and reconstituted with autologous PBMC: first clinical experience and evidence of an immune response

“…Recently, different groups have identified an approach that exploits the increased sensitivity of lymphocytes to respond to antigenic stimuli when they are placed under conditions of homeostasis-driven proliferation [ 9 - 13 , 18 ] (reviewed in [ 19 , 20 ]). In the preclinical setting, this was modeled by vaccinating lymphopenic mice with a GM-CSF gene-modified melanoma cell line following reconstitution with naïve spleen cells.…”

T cell immune reconstitution following lymphodepletion

“…Adoptive transfer of transgenic melanoma-antigen specific T cells blocked tumor growth better in irradiated hosts than in intact hosts [9]. The superior CD8 antitumor response after immune depletion was further enhanced by increasing the cytoreductive radiation dose in a syngeneic stem cell transplant model [10,111]. This CD8+-mediated antitumor immunity was shown to be dependent on the presence of IL-7 and IL-15 using cytokine knockout mice, implicating these normal homeostasis mechanisms in the generation of antitumor responses by adoptive T cell transfer [9].…”

Cancer Vaccines for Hematologic Malignancies

“…In an attempt to model the integration of GM-CSF-based tumor cell vaccines in the autologous BMT setting, we recently established a syngeneic murine model. 96 This model demonstrates the effectiveness of antitumor vaccines as measured by the ability to cure a pre-established tumor burden when such vaccines were administered early posttransplant, long before full immune reconstitution. Surprisingly, the ability to elicit effective antitumor responses was significantly greater in the transplanted mice than in their nontransplanted counterparts with an equivalent tumor burden.…”