There is a critical need to delineate pathobiological correlates of chronic GVHD (cGVHD) and to develop new strategies to prevent and treat cGVHD. These strategies must control both acute and cGVHD, minimize risk of opportunistic infection, and maintain GVL. To do this our understanding of GVHD pathobiology must be broadened. For instance, recognizing that antibody responses to HY antigens are important in cGVHD physiology underscores the need to develop more tools to identify somatic mHA as a step toward the integration of mHA and genetic determinates of immune reactivity. Thus, a coordinated effort combining 1) clinical trials, 2) the development of a relevant animal model to study pathobiology and in which new therapies can be tested, and 3) further elucidation of the immunologic basis of human cGVHD is essential. Project 1 will develop strategies to prevent cGVHD by targeting B cells and regulatory T cells. The first strategy is a novel anti-CD20 prophylaxis regimen, while the second strategy will allow the expansion of regulatory T cells by eliminating calineurin inhibitors from GVHD prophylaxis.
The second aim i s to prevent hepatic VOD by adjusting the therapy to avoid hepatic injury or by preventing vascular complications using the novel agent, defibrotide. Finally, two complementary approaches to treat steroid-resistant GVHD will be assessed: 1) coordinate inhibition of both B and T cells, and 2) expansion of regulatory T cells with ultra low dose IL-2. Project 2 will expand its studies of a new, clinically relevant mouse model of cGVHD. This will allow the pathobiology of cGVHD to be explored in the first aim, while the second aim models therapeutic approaches that can be clinically assessed in Project 1. Project 3 will continue its work in minor histocompatitbility antigen discovery moving now from sex-chromosome associated proteins to more generalized antigen discovery. This project will also develop GVHD-specific biomarkers that will allow more precise prediction of who will develop cGVHD as well as allow the therapy to be closely monitored to reduce toxicity. Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective.

Public Health Relevance

Hematopoietic stem cell transplantation is the only curative therapy for many patients with blood disorders. Worldwide, >16,000 allogeneic HSCT are performed yearly. Realization of the full potential of HSCT requires elimination of HSCT related complications -particularly acute and cGVHD. Traditional means to control GVHD, particularly cGVHD are only partially effective. This Program Project will focus on increasinng our understanding of cGVHD developing novel, more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA142106-10
Application #
8468127
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Merritt, William D
Project Start
2009-04-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$1,755,269
Indirect Cost
$602,037
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Borges, Christopher M; Reichenbach, Dawn K; Kim, Beom Seok et al. (2016) Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival. Transpl Int 29:930-40
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
Alho, Ana C; Kim, Haesook T; Chammas, Marie J et al. (2016) Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood 127:646-57
Schönle, Anne; Hartl, Frederike A; Mentzel, Jan et al. (2016) Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood 127:1930-9
Flynn, Ryan; Paz, Katelyn; Du, Jing et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-54
Zeiser, Robert; Blazar, Bruce R (2016) Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood 127:3117-26
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
Souroullas, George P; Jeck, William R; Parker, Joel S et al. (2016) An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 22:632-40
Koreth, John; Kim, Haesook T; Jones, Kyle T et al. (2016) Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood 128:130-7
Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye et al. (2016) Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells. JCI Insight 1:e89278

Showing the most recent 10 out of 161 publications