Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with hematologic malignancies and marrow failure. The full potential of HSCT is limited by transplant related complications -particularly acute and chronic GVHD (cGVHD). Traditional means to control GVHD, particularly cGVHD, are only partially effective. Despite excellent control of acute GVHD, 50-70% of patients develop cGVHD. Chronic GVHD is the primary late complication of HSCT. The heterogeneity of manifestations and late onset has led to a situation where research lags behind clinical needs. The importance of cGVHD is increasingly relevant as 1) improvements in HSCT technology allow the use of older donors to transplant older patients, 2) the incidence of cGVHD increased due to greater use of peripheral blood as a stem cell source, and 3) improvements in supportive care result in less nonrelapse mortality and thus more patients alive in the late time periods when cGVHD occurs. This is an opportunity to embark on novel studies to leverage new information on the pathobiology of GVHD. The importance of B cells and regulatory T cells (Treg) is increasingly clear, but there has been little effort to directly manipulate B cell and Treg function in humans. We now know that B cells work with T cells in a coordinated fashion to produce cGVHD. Project 1 includes three Specific Aims (SA) including 5 projects to develop new strategies to prevent and treat GVHD. SA1a is a novel approach to prevent cGVHD in patients without active GVHD using monoclonal anti-CD20 to target the B cell component of cGVHD. In SA1b the goal is to eliminate calineurin inhibitors (CNI) from GVHD prophylaxis. CNI have undesirable intrinsic toxicity, and they inhibit Treg in a counterproductive fashion. By using CNI-free regimens, the expansion of Treg is facilitated to reduce both allo- and autoimmunity, and thus the overall risk of both acute and cGVHD. In SA 2 strategies to prevent a major complication of HSCT, hepatic VOD are assessed. In SA 3, two complementary approaches to treat steroid-resistant cGVHD will be evaluated: 1) by coordinately inhibiting both B and T cells with low dose anti-CD52 monoclonal antibody, and 2) by expansion of Treg with ultra low dose IL-2.

Public Health Relevance

The importance of cGVHD is increasingly relevant as 1) improvements in HSCT technology allow the use of older donors to transplant older patients, 2) the incidence of cGVHD increased due to greater use of peripheral blood as a stem cell source, and 3) improvements in supportive care result in less nonrelapse mortality and thus more patients alive in the late time periods when cGVHD occurs. This is an opportunity to embark on novel studies to leverage new information on the pathobiology of GVHD.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA142106-10
Application #
8468131
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$263,342
Indirect Cost
$90,324
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

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