Immune responses are critical in determining the outcome of allogeneic hematopoietic cell transplantation (HCT). Allogeneic immune responses of donor cells against host antigens lead to both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). In contrast, deficient reconstitution of immune responsiveness leads to opportunistic infections with a variety of microbial and viral pathogens. Inadequate recognition and destruction of residual tumor cells by a newly engrafted donor immune system also permits recurrence of a patient's underlying malignancy. An accurate understanding of immune reconstitution after allogeneic HSCT is necessary to design and implement strategies to regulate immune responsiveness. Hopefully, by so doing, anti-tumor reactivity can be enhanced while minimizing complications such as GVHD and immune deficiency. This Program Project will build on the central theme of reconstitution and manipulation of immune function post-transplant that we have pursued vigorously during the past funding cycles of the Program. Project 1 will focus on vaccination strategies designed to stimulate anti-leukemic immunity without producing an indiscriminate allogeneic response. Based upon studies performed in the non-transplant setting which have confirmed safety and induction of robust immunologic activity, vaccinations with recipient-derived irradiated autologous tumor cells engineered to secrete GM-CSF will be administered to high risk patients after non-myeloablative allogeneic transplantation. Examination of T and B cell responses to vaccination will hopefully lead to the identification of new genes and antigens which can serve as targets for future vaccination strategies. Determining and establishing the optimal environmental milieu to maximize a specific immune response will be critical to the success of this Project. Regulatory T cells are thought to play an important role in the development and control of allogeneic immune responses (GVH and GVL reactions) post-transplant, and it is likely they will impact on immune responses to other antigens as well. Attempts to generate specific immunity against microbial pathogens or residual tumor cells may be profoundly influenced by the activity of these regulatory cells. Project 2 will focus on the characterization of regulatory T cells and their correlation with GVHD and anti-tumor immune responses in patients undergoing HCT. Project 3 will develop experimental murine models to study the impact of exogenous administration of these regulatory T cells on allogeneic and tumor specific responses. This is highly interactive Program will bring together experimental animal models, patient based clinical trials, and correlative laboratory investigation to better understand the regulation of immune responses so that they may be modulated to improve transplant outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
3U19AI029530-18S1
Application #
8054706
Study Section
Special Emphasis Panel (ZAI1-AWA-I (J1))
Program Officer
Bridges, Nancy D
Project Start
1990-08-01
Project End
2011-03-31
Budget Start
2010-05-04
Budget End
2011-03-31
Support Year
18
Fiscal Year
2010
Total Cost
$799,185
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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

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