Allogeneic hematopoietic stem cell transplantation (HSCT) is currently used for the treatment of a variety hematologic malignancies. Recently, there has been renewed interest in HSCT for solid cancers as well as solid organ transplantation and autoimmunity. However, the occurrence of graft-versus-host disease (GVHD), in both acute, and with increasing prevalence, chronic forms significantly limits the use and efficacy of this approach. Both forms of GVHD are driven by donor T cells and cytokines. While chronic GVHD has been emerging more and more in HSCT, there have been little preclinical studies assessing its control and concurrent effects on beneficial graft-versus-tumor (GVT) effects. We and others have shown that cytokines such as interferon-gamma (IFN?) and TNF1 play pivotal and dual roles in GVH/GVT responses. Further, molecular targeting of GVHD via proteasome or NFkB inhibition represents a novel means not only modulate GVHD but also promote GVT but mechanisms of action as well as effects in chronic GVHD remain not known. To build on our published and preliminary data we propose 3 Specific Aims to dissect both efficacy and mechanism of these two approaches - cytokine manipulation and molecular targeting.
Specific Aim 1 will seek to dissect the roles of the IFN?/TNFa/IL-17 cytokine pathways in acute GVHD models through modulation by clinically translatable approaches by either by siRNA or antibody blockade. We will then combine with molecular targeting approaches to these models in an attempt to further control GVHD pathobiology using the proteasome inhibitor, bortezomib and a novel NFkB inhibitor.
Specific Aim 2 will then determine the role of these cytokines in chronic GVHD models looking at skin and lung pathology and assess the efficacy of molecular targeting in not only prevention but also treatment of active disease.
Specific Aim 3 will then use both solid and hematologic cancer models and assess the efficacy of these approaches on the prevention/control of GVHD and potential promotion of GVT. This proposal should not shed valuable insights on both acute and chronic GVHD but also allows for preclinical assessment of translatable approaches in their control as well as assessment in orthotopic cancer models.

Public Health Relevance

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently used for the treatment of a variety of hematologic malignancies and shows promise for the treatment of solid cancers such as renal cell carcinomas. However, significant obstacles still limit the safety and efficacy of this procedure. Paramount among these complications is the occurrence of graft-versus host disease (GVHD) and tumor relapse. This proposal will develop pre-clinical strategies to improve the application of allogeneic HSCT to reduce the incidence and severity of both chronic and acute GVHD and augment graft versus tumor activity for the treatment of solid tumors as well as hematologic malignancies

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA102282-10S1
Application #
8653127
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Ogunbiyi, Peter
Project Start
2003-07-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$55,904
Indirect Cost
$15,266
Name
University of California Davis
Department
Dermatology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Pai, Chien-Chun Steven; Chen, Mingyi; Mirsoian, Annie et al. (2014) Treatment of chronic graft-versus-host disease with bortezomib. Blood 124:1677-88
Ames, Erik; Harouna, Salif; Meyer, Colin et al. (2012) The triterpenoid CDDO-Me promotes hematopoietic progenitor expansion and myelopoiesis in mice. Biol Blood Marrow Transplant 18:396-405
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Koreth, John; Alyea, Edwin P; Murphy, William J et al. (2009) Proteasome inhibition and allogeneic hematopoietic stem cell transplantation: a review. Biol Blood Marrow Transplant 15:1502-12
Hallett, William H D; Ames, Erik; Motarjemi, Milad et al. (2008) Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J Immunol 180:163-70
Li, Minghui; Sun, Kai; Welniak, Lisbeth A et al. (2008) Immunomodulation and pharmacological strategies in the treatment of graft-versus-host disease. Expert Opin Pharmacother 9:2305-16
Sun, Kai; Li, Minghui; Sayers, Thomas J et al. (2008) Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation. Blood 112:1522-9
Hallett, William H D; Ames, Erik; Alvarez, Maite et al. (2008) Combination therapy using IL-2 and anti-CD25 results in augmented natural killer cell-mediated antitumor responses. Biol Blood Marrow Transplant 14:1088-99
Sun, Kai; Li, Minghui; Konopleva, Marina et al. (2007) The synthetic triterpenoid, CDDO, suppresses alloreactive T cell responses and reduces murine early acute graft-versus-host disease mortality. Biol Blood Marrow Transplant 13:521-9

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