The goal of hematopoietic cell transplantation (HCT) for hematologic malignancies is sustained eradication of disease. While high dose chemo/radiotherapy can contribute to tumor destruction, it is clear from pre-clinical models and clinical studies that immune mediated allogeneic effects, termed graft-vs-leukemia (GVL) effects, are central to the therapeutic effect of allogeneic HCT. Successful trials of adoptive immunotherapy with donor lymphocytes infusions (DLI) and promising reports of non-myeloablative stem cell transplants (NST) have shifted the therapeutic focus of allogeneic hematopoietic cell transplantation (HCT) away from high dose chemo/radiotherapy and toward anti-tumor effects mediated by the donor's immune system. Initial attempts to augment this graft-vs-leukemia (GVL) activity after NST have included early withdrawal of immune suppression or early administration of unfractionated donor lymphocyte infusions. The success of these strategies has been limited by the accelerated development of GVHD. If leukemia specific responses rather than broad allogeneic reactivity could be induced, then it might be possible to promote GVL in the absence of GVHD. The studies proposed in this Project will examine strategies aimed at inducing and augmenting anti-leukemic immunity early after allogeneic transplantation without necessarily stimulating broad allo-reactive responses. Based upon murine models and human trials that have established the feasibility, safety, and immunologic activity of GM-CSF secreting autologous tumor vaccines, we will initiate a series of clinical trials utilizing this strategy in the allogeneic transplant setting. We hypothesize that paracrine secretion of GM-CSF by the irradiated/modified leukemia cells should attract professional antigen presentation cells (APCs), such as dendritic cells, to the leukemia cells, and stimulate these APCs to present leukemia antigens to donor lymphocytes, thereby triggering a leukemia specific allo-immune effect. We hope from these trials to establish the optimal immunologic milieu to promote immunization early after transplantation. We will correlate functional and phenotypic parameters of immune reconstitution with vaccine mediated induction of tumor specific immunity, paying particular attention to the role of regulatory T cells. Examination of T and B cell responses to vaccination will hopefully lead to discovery of genes that could serve as targets for subsequent vaccination protocols. Further augmentation of tumor specific immunity through CTLA-4 antibody blockade will be explored in the allogeneic transplant setting in patients who have or have not been previously immunized with GM-CSF based vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-AWA-I (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Kim, Haesook T; Zhang, Mei-Jie; Woolfrey, Ann E et al. (2016) Donor and recipient sex in allogeneic stem cell transplantation: what really matters. Haematologica 101:1260-1266
Armand, Philippe; Kim, Haesook T; Sainvil, Marie-Michele et al. (2016) The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol 173:96-104
Armand, Philippe; Kim, Haesook T; Logan, Brent R et al. (2014) Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 123:3664-71
Armand, Philippe; Kim, Haesook T; Virtanen, Johanna M et al. (2014) Iron overload in allogeneic hematopoietic cell transplantation outcome: a meta-analysis. Biol Blood Marrow Transplant 20:1248-51
Kim, Haesook T; Armand, Philippe (2013) Clinical endpoints in allogeneic hematopoietic stem cell transplantation studies: the cost of freedom. Biol Blood Marrow Transplant 19:860-6
Matsuoka, Ken-ichi; Koreth, John; Kim, Haesook T et al. (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 5:179ra43
Armand, Philippe; Gibson, Christopher J; Cutler, Corey et al. (2012) A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 120:905-13
Armand, Philippe; Kim, Haesook T; Zhang, Mei-Jie et al. (2012) Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant 18:280-8
Zilberberg, Jenny; Friedman, Thea M; Dranoff, Glenn et al. (2011) Treatment with GM-CSF secreting myeloid leukemia cell vaccine prior to autologous-BMT improves the survival of leukemia-challenged mice. Biol Blood Marrow Transplant 17:330-40
Kawano, Yutaka; Kim, Haesook T; Matsuoka, Ken-Ichi et al. (2011) Low telomerase activity in CD4+ regulatory T cells in patients with severe chronic GVHD after hematopoietic stem cell transplantation. Blood 118:5021-30

Showing the most recent 10 out of 25 publications