ETI

Pilot Project

Miriam Merad
Miriam Merad, MD, PhD
Associate Professor Gene and Cell Medicine
Associate Professor Medicine, Hematology and Medical Oncology
Mount Sinai School of Medicine

Host Dendritic Cell Vaccination For Prevention Or For Treatment Of Relapsed Disease After Allogeneic Hematopoietic Cell Transplantation In Patients With Hematological Malignancies

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative treatment for many patients with high-risk hematological malignancies. The success of allo-HCT is largely based on immunologic graft-versus-tumor effects mediated by allogeneic T lymphocytes present in the graft. Long-term remission is achieved in a proportion of patients, but not all. Of those patients (approximately one-third) whose disease remains refractory or who relapse after allo-HCT, a proportion can be salvaged by donor lymphocyte infusion. The success of donor lymphocyte infusion is further evidence of the importance of allo-immune responses in hematopoietic transplantation.

There is ample evidence in animal models of transplantation that host dendritic cells (DCs) play a critical role in priming donor T cells to induce anti-tumor response at the time of transplant and following donor lymphocyte infusion. The importance of host DCs in priming donor T cells relates to direct presentation of host antigens. However, host DCs are progressively replaced by donor-derived DCs after allo-HCT, and the opportunity for donor lymphocytes to interact with directly presented host antigens declines. This may be one reason that donor lymphocyte infusion responses attenuate over time and fail in some patients.

According to this argument, it should be possible to enhance graft versus tumor responses by infusing additional host DCs to transplant patients. Therefore we have devised a clinical trial in which we propose to inject host DCs in patients that have minimal residual disease or that relapse after allo-HCT. The overall goal of this application is to examine whether infusion of host DCs either alone or in addition to donor lymphocyte infusion can induce therapeutic immunity in patients that relapse after allo-HCT and to identify novel immunogenic epitopes that trigger allogeneic graft versus tumor responses in the absence of graft versus host disease.