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 graftversus-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.

Vascular Endothelial Growth Factor-D–Mediated Blockade of Regulatory T Cells within Tumors Is Induced by Hematopoietic Stem Cell Transplantation

“…However, no overt toxicity was observed for the recipient mice. The immunogenic DCs at the tumor sites were able to capture both tumor-associated Ags and normal self-Ags shared by tumor and normal cells, whereas resting host DCs away from the tumor site present only normal self-Ags and may induce tolerance or exhaustion of host-reactive T cells (32,33). Alternatively, the percentage of Foxp3…”

Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells

“…17,46 GM-CSF, as a DC promoting cytokine, has been widely employed in cancer immunotherapy experimentally and clinically. 20,31,[47][48][49][50][51][52] Our previous study demonstrated that GM-CSF treatment significantly expanded the number of antigen-expressing DCs for antigen presentation. 27 However, the effects of GM-CSF on enhanced activation of antigen-specific T cells appeared to be short lived in tumor-bearing HA-BMT mice in the absence of DC activation adjuvant.…”

Anti‐tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution

“…New strategies that employ post-transplant tumor vaccination and adoptive immunotherapy with donor-derived tumor-reactive T cells could potentially enhance the GVT effects [37]. A recent preclinical study strongly supported tumor vaccination in conjunction with donor lymphocyte infusion after NST [38], and provides the basis for novel clinical trials aimed at skewing the T cell repertoire towards high reactivity to tumor antigens during immune reconstitution. In light of these findings and our previous and current results, the lymphopenic period could provide an important window of opportunity for the design of novel immunotherapy strategies for patients with minimal residual disease.…”