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 #
5P01CA142106-09
Application #
8257940
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Merritt, William D
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2012-05-09
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$1,867,308
Indirect Cost
$640,465
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Bachireddy, Pavan; Hainz, Ursula; Rooney, Michael et al. (2014) Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. Blood 123:1412-21
Dubovsky, Jason A; Flynn, Ryan; Du, Jing et al. (2014) Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 124:4867-76
Koreth, John; Kim, Haesook T; Nikiforow, Sarah et al. (2014) Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival. Biol Blood Marrow Transplant 20:1516-21
Herrera, Alex F; Kim, Haesook T; Bindra, Bhavjot et al. (2014) A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. Biol Blood Marrow Transplant 20:1737-43
Gazourian, Lee; Rogers, Angela J; Ibanga, Ruby et al. (2014) Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Am J Hematol 89:404-9
Socié, Gérard; Ritz, Jerome (2014) Current issues in chronic graft-versus-host disease. Blood 124:374-84
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
Alexander, Kylie A; Flynn, Ryan; Lineburg, Katie E et al. (2014) CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest 124:4266-80
Kim, Haesook T; Frederick, David; Armand, Philippe et al. (2014) White blood cell recovery after allogeneic hematopoietic cell transplantation predicts clinical outcome. Am J Hematol 89:591-7
Pai, Chien-Chun Steven; Chen, Mingyi; Mirsoian, Annie et al. (2014) Treatment of chronic graft-versus-host disease with bortezomib. Blood 124:1677-88

Showing the most recent 10 out of 68 publications