Grant Details
Grant Number: |
5R01CA231141-05 Interpret this number |
Primary Investigator: |
Afshar-Kharghan, Vahid |
Organization: |
University Of Tx Md Anderson Can Ctr |
Project Title: |
Genetics of Graft-Versus-Host Disease |
Fiscal Year: |
2022 |
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for many advanced
hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of
the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues,
and initiating an alloimmune response resulting in damage to many organs including the skin, GI tract, and liver
in recipient. More than half of all allo-HSCT recipients develop different degrees of GVHD (grade I-IV). About
20% of recipients develop severe GVHD (grade III-IV) that is associated with a very high morbidity and mortality.
The most important factor determining the severity of GVHD is the genetic disparities between donors and
recipients, as is reflected in HLA haplotypes that are routinely checked for donor selection. But even when donors
and recipients are HLA-identical many recipients develop severe GVHD. As a result, non-HLA antigens are
important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence
of an interaction between antigens present in one individual with the immune system of another individual. As a
result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To
determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide
Association Studies (GWAS) in 3,000 patients who underwent allo-HSCT and in their respective donors (6000
DNA samples) that are provided to us by the National Marrow Donor Program (NMDP) and the Center for
International Blood and Marrow Transplant Research (CIBMTR). This part of our grant is approved by the Center
for Inherited Disease Research (CIDR) and will be conducted in their sequencing facility. We expect that 3000
recipients will be stratified into 1200 subjects with moderate to severe acute GVHD (grades II-IV) versus 1800
individuals with none to mild GVHD (grade 0-I). We will also include the existing GWAS and clinical outcome
data on 7047 donor/recipient pairs available from two previous studies to augment our cohort with an estimated
2830 pairs with grade II-IV and 4244 pairs with grade 0-I GVHD, and investigate an association between the
severity of acute GVHD and genotypes in donors or recipients, or mismatch of certain genotypes (other than
HLA). In the second aim, we will validate the association between high risk genotypes detected in the aim 1 and
severe GVHD in 1,750 donors and 1,750 recipients of allo-HSCT, and perform the joint analysis with the
discovery samples (an estimated 4730 pairs with grade II-IV vs 7094 pairs with Grade 0-I GVHD). We will
determine the frequency of 5000 single nucleotide polymorphisms (SNP), that GWAS in the aim 1 showed to be
associated with severe GVHD and correlate it to the severity of GVHD. In the third aim, we will investigate the
functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD
in mixed lymphocyte reaction (MLR), as an Ex vivo surrogate for an alloimmune response.
Publications
Real-world outcomes with tisagenlecleucel in aggressive B-cell lymphoma: subgroup analyses from the CIBMTR registry.
Authors: Landsburg D.J.
, Frigault M.J.
, Heim M.
, Foley S.R.
, Hill B.
, Schofield G.
, Jacobson C.A.
, Jaglowski S.
, Locke F.L.
, Ram R.
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Source: Journal For Immunotherapy Of Cancer, 2025-02-09 00:00:00.0; 13(2), .
EPub date: 2025-02-09 00:00:00.0.
PMID: 39924174
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Authors: Kermany D.S.
, Ahn J.Y.
, Vasquez M.
, Zhang W.
, Wang L.
, Liu K.
, Xu Z.
, Cho M.S.
, Carlos-Alcalde W.
, Lee H.
, et al.
.
Source: Cancer Communications (london, England), 2025-01-03 00:00:00.0; , .
EPub date: 2025-01-03 00:00:00.0.
PMID: 39749685
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, DeFor T.E.
, Cole K.
, Cirrone F.
, King S.
, Suarez-Londono A.
, Yaghmour G.
, Boisclair S.
, Bupp C.
, Spellman S.R.
.
Source: Transplantation And Cellular Therapy, 2024 Nov; 30(11), p. 1092-1098.
EPub date: 2024-08-30 00:00:00.0.
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, McCann M.
, Yusuf R.A.
, Hengen M.
, Auletta J.J.
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Source: Transplantation And Cellular Therapy, 2024 Sep; 30(9), p. 864-875.
EPub date: 2024-06-21 00:00:00.0.
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, Liang X.
, Dong J.F.
, Cruz M.A.
, Ma Q.
, Afshar-Kharghan V.
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Source: Journal Of Cellular And Molecular Medicine, 2024 Jul; 28(13), p. e18457.
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, Ghobadi A.
, Ahmed S.
, Miklos D.B.
, Perales M.A.
, Munoz J.
, Fingrut W.B.
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, Saunders P.M.
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Source: Biorxiv : The Preprint Server For Biology, 2024-05-05 00:00:00.0; , .
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, Wang H.L.
, Hu Z.H.
, Locke F.L.
, Siddiqi T.
, Jacobson C.A.
, Ahmed S.
, Miklos D.B.
, Lin Y.
, Hill B.T.
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Source: American Journal Of Hematology, 2024 May; 99(5), p. 880-889.
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, Patel M.
, Shah K.
, Habibollahi P.
, Metwalli Z.
, Gurusamy V.
, Gupta S.
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Source: Cardiovascular And Interventional Radiology, 2024 May; 47(5), p. 556-566.
EPub date: 2024-03-28 00:00:00.0.
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Source: Journal Of Thrombosis And Haemostasis : Jth, 2023 Aug; 21(8), p. 2202-2212.
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Authors: Shi J.
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, Choi J.
, Matsuo K.
, Chen T.Y.
, Dai J.
, Hung R.J.
, Chen K.
, Shu X.O.
, Kim Y.T.
, et al.
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Source: Nature Communications, 2023-05-26 00:00:00.0; 14(1), p. 3043.
EPub date: 2023-05-26 00:00:00.0.
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Source: Melanoma Research, 2023-02-20 00:00:00.0; , .
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Authors: Qiao W.
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, Feng C.
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, Jin J.
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Source: Experimental Hematology & Oncology, 2022-09-16 00:00:00.0; 11(1), p. 58.
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, Tan Y.
, Ivan C.
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, Giralt S.
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, Aljurf M.
, Banerjee R.
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Source: Transplantation And Cellular Therapy, 2022 Feb; 28(2), p. 83.e1-83.e9.
EPub date: 2021-11-12 00:00:00.0.
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Of vascular defense, hemostasis, cancer, and platelet biology: an evolutionary perspective.
Authors: Menter D.G.
, Afshar-Kharghan V.
, Shen J.P.
, Martch S.L.
, Maitra A.
, Kopetz S.
, Honn K.V.
, Sood A.K.
.
Source: Cancer Metastasis Reviews, 2022-01-12 00:00:00.0; , .
EPub date: 2022-01-12 00:00:00.0.
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Source: Human Genetics, 2022-01-04 00:00:00.0; , .
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Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer.
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.
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, Balkrishnan R.
, Burns L.
, Devine S.
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.
Source: Transplantation And Cellular Therapy, 2021 10; 27(10), p. 869.e1-869.e9.
EPub date: 2021-07-02 00:00:00.0.
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Authors: Hahn T.
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, Preus L.M.
, Karaesmen E.
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, Clay-Gilmour A.I.
, Zhu Q.
, Wang Y.
, Yan L.
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.
Source: Eclinicalmedicine, 2021 Oct; 40, p. 101093.
EPub date: 2021-08-25 00:00:00.0.
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, Hamadani M.
, Kumar A.
, Dreger P.
, Friedberg J.W.
, Dreyling M.
, Kahl B.
, Jerkeman M.
, Kharfan-Dabaja M.A.
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, et al.
.
Source: Transplantation And Cellular Therapy, 2021 Sep; 27(9), p. 720-728.
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, Steinert P.
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EPub date: 2021-04-22 00:00:00.0.
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, Vierra-Green C.
, Barker D.J.
, Auletta J.
, Bhatt V.R.
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Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2021-07-20 00:00:00.0; 39(21), p. 2397-2409.
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, Stock W.
, Advani A.
, Luger S.
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, Chhabra S.
, D'Souza A.
, Dahi P.B.
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.
Source: Transplantation And Cellular Therapy, 2021 Jul; 27(7), p. 617.e1-617.e7.
EPub date: 2021-04-06 00:00:00.0.
PMID: 33836312
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Losing control to bad relatives.
Authors: Afshar-Kharghan V.
.
Source: Blood, 2021-06-24 00:00:00.0; 137(25), p. 3462-3463.
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Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis.
Authors: Goldsmith S.R.
, Abid M.B.
, Auletta J.J.
, Bashey A.
, Beitinjaneh A.
, Castillo P.
, Chemaly R.F.
, Chen M.
, Ciurea S.
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, et al.
.
Source: Blood, 2021-06-10 00:00:00.0; 137(23), p. 3291-3305.
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, Shah N.N.
, Hsu J.W.
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Source: Transplantation And Cellular Therapy, 2021 Jun; 27(6), p. 503.e1-503.e8.
EPub date: 2021-03-09 00:00:00.0.
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.
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Authors: Sharma A.
, Badawy S.M.
, Suelzer E.M.
, Murthy H.S.
, Prasad P.
, Eissa H.
, Carpenter P.A.
, Hamadani M.
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.
Source: Transplantation And Cellular Therapy, 2021 05; 27(5), p. 380-388.
EPub date: 2021-01-28 00:00:00.0.
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, Ahn K.W.
, Dandoy C.
, Perales M.A.
, Wood W.A.
, Logan B.
, Riches M.
, Rizzo J.D.
.
Source: Transplantation And Cellular Therapy, 2021-04-22 00:00:00.0; , .
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The effect of platelet G proteins on platelet extravasation and tumor growth in the murine model of ovarian cancer.
Authors: Cho M.S.
, Li J.
, Gonzalez-Delgado R.
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, Vasquez M.
, He T.
, He Y.
, Liu K.
, Sasano T.
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Authors: Sharma A.
, Badawy S.M.
, Suelzer E.M.
, Murthy H.S.
, Prasad P.
, Eissa H.
, Carpenter P.A.
, Hamadani M.
, Labopin M.
, Schoemans H.
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.
Source: Bone Marrow Transplantation, 2021 Apr; 56(4), p. 786-797.
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Serious Adverse Events in Related Donors: A Report from the Related Donor Safe Study.
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, Chitphakdithai P.
, Miller J.P.
, Kobusingye H.
, Logan B.R.
, Linenberger M.
, Artz A.S.
, Haight A.E.
, Jacobsohn D.A.
, Litzow M.R.
, et al.
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Source: Transplantation And Cellular Therapy, 2021 Apr; 27(4), p. 352.e1-352.e5.
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Is autologous transplant in relapsed DLBCL patients achieving only a PET+ PR appropriate in the CAR T-cell era?
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, Ahn K.W.
, Litovich C.
, He Y.
, Sauter C.
, Fenske T.S.
, Hamadani M.
.
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, Costa L.
, Goodman S.
, Estrada-Merly N.
, Lee C.
, Hildebrandt G.
, Gergis U.
, Farhadfar N.
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, Sees J.A.
, Fernandez-Viña M.
, Abid M.B.
, Askar M.
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, Getz K.D.
, Hemmer M.
, Huang Y.V.
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, Kitko C.L.
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Source: Transplantation And Cellular Therapy, 2021 02; 27(2), p. 177.e1-177.e8.
EPub date: 2020-12-21 00:00:00.0.
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