Allogeneic stem-cell transplantation (SCT) is effective in part due to the graft-versus-tumor (GvT) potential of the donor graft~ however, successful SCT is often limited by graft-versus-host disease (GvHD). Acute GvHD is a major cause of morbidity and mortality after allogeneic SCT for blood cancers, occurring in 30-70% of transplants. With 28,000 allogeneic transplants performed worldwide each year, 15% of deaths following allogeneic SCT are a direct result of GvHD. Existing modalities for both prevention and treatment of GvHD are immunosuppressive, impair immune recovery and may limit the GvT effect. Our prior work has demonstrated that blockade of CCR5, a chemokine receptor, significantly decreased visceral GvHD in humans. The overarching goal of the current proposal is to exploit pharmacologic contro of lymphocyte trafficking after allogeneic SCT for therapeutic benefit. The central hypothesis is that T-cell trafficking plays a central role in the three major clinical and immunologic outcomes of allogeneic SCT - GvHD, GvT and reconstitution of a healthy immune system. To test this hypothesis, a clinical trial will be conducted in order to simultaneously investigate mechanistic and therapeutic endpoints. The experimental approach revolves around a phase II trial of extended CCR5 blockade in unrelated donor SCT for patients with blood cancers.
Aim 1 will determine the clinical and immunologic effects of extended CCR5 blockade after allogeneic SCT and identify predictors of response using appropriate pharmacodynamic and genotypic methods.
Aim 2 will determine the effect of extended CCR5 blockade on immune recovery and anti-tumor immunity by conducting a series of validated assays.
Aim 3 will identify the role of CCR5 in determining the tissue-tropism of effector T-cells, using a novel sequencing technology to survey the entire repertoire of T-cells and characterize their phenotype. The use of samples from 2 clinical trials together with control samples from a biospecimen bank will add power to the analysis of all 3 aims. This proposal is highly translational, revolves around a human clinical trial, and takes advantage of appropriate immune pharmacodynamic methods, developed specifically for this proposal, and genomic sequencing of T-cell clones to identif the chemokine receptor signature that is involved in T-cell recruitment into specific tissues. Combining patient-oriented research with state of the art immunologic assays will have a dual role - fuel our basic understanding of trafficking mechanisms in transplantation and cancer immunology, and at the same time change the standard of care by introducing a new class of targeted, minimally immunosuppressive medications to the field. If successful, this proposal may lead to a paradigm shift in the prevention of GvHD, setting the stge for a randomized clinical trial that will rely on the same clinical and immunologic endpoints to measure its success.

Public Health Relevance

The aim of this proposal is to determine the role of lymphocyte chemotaxis in determining the outcomes of allogeneic stem-cell transplantation by studying the clinical and immunologic impact of CCR5 blockade as a proof of concept. The long-term goal is to develop effective ways to control lymphocyte recruitment in order to decrease the incidence of graft-versus-host disease, improve immune recovery and maintain effective anti- tumor immunity after stem-cell transplantation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23CA178202-01
Application #
8568267
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
2013-09-12
Project End
2016-08-31
Budget Start
2013-09-12
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$174,744
Indirect Cost
$12,944
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Yam, Clinton; Crisalli, Lisa; Luger, Selina M et al. (2016) Unrelated donors are associated with improved relapse-free survival compared to related donors in patients with myelodysplastic syndrome undergoing reduced intensity allogeneic stem cell transplantation. Am J Hematol 91:883-7
Meng, Lijun; Bai, Zhenjiang; He, Shan et al. (2016) The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation. J Immunol 196:1070-80
Widman, Adam; Reshef, Ran (2016) Precision in donor selection: Identifying ideal stem-cell donors through their T cells. Exp Hematol 44:1020-1023
Mochizuki, Kazuhiro; Meng, Lijun; Mochizuki, Izumi et al. (2016) Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice. Blood 127:3270-80
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Ganetsky, Alex; Miano, Todd A; Hughes, Mitchell E et al. (2015) Lack of a significant pharmacokinetic interaction between maraviroc and tacrolimus in allogeneic HSCT recipients. J Antimicrob Chemother 70:2078-83
Karimi, Mobin A; Bryson, Jerrod L; Richman, Lee P et al. (2015) NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT. Blood 125:3655-63
Luskin, M R; Heil, D S; Tan, K S et al. (2015) The Impact of EBV Status on Characteristics and Outcomes of Posttransplantation Lymphoproliferative Disorder. Am J Transplant 15:2665-73
Reshef, R; Porter, D L (2015) Reduced-intensity conditioned allogeneic SCT in adults with AML. Bone Marrow Transplant 50:759-69

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