Nelson Chao

Overview:

My research interests are in two broad areas, clinical hematopoietic stem cell and cord blood transplantation and in the laboratory studies related to graft vs. host disease and immune reconstitution. On the clinical side we are currently conducting approximately 50 different clinical protocols ranging from preparatory regimens, supportive care studies and disease specific protocols. Most of these clinical studies are centered around studies of the sources of stem cells and the methods to improve the long term outcome. There are exploratory protocols for novel therapies such as dendritic cell therapy for several malignancies, antiangiogenesis therapy, graft engineering to prevent graft-versus-host disease and antigen specific T cells or non specific NK cells to prevent relapse. Moreover a strong focus of the program is to develop cord-blood transplantation for adult patients with hematologic malignancies. The laboratory studies center on understanding the immunological events that occur with graft-vs-host disease and methods to prevent this disease. The current efforts focus on understanding murine reconstitution following transplantation, use of a peptide polymer to block MHC class II recognition of minor histocompatibility antigens, use of T cell engineering to prevent graft-versus-host disease at the same time preserving a graft-versus-malignancy effect.

For more information see http://ed-media.mc.duke.edu/BMT.nsf

Positions:

Donald D. and Elizabeth G. Cooke Cancer Distinguished Research Professor

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Professor in Immunology

Immunology
School of Medicine

Research Professor of Global Health

Duke Global Health Institute
Institutes and Provost's Academic Units

Professor in Pathology

Pathology
School of Medicine

Chief, Division of Cell Therapy in the Department of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1981

Yale University

Medical Resident, Medicine

Stanford University

Fellow in Oncology, Medicine

Stanford University

Grants:

Clinical Presentation, Treatment, and Outcomes of Grade 2-4 Acute Graft Versus Host Disease (GVHD) Patients after Allogeneic Hematopoietic Stem Call Transplants (HSCT): A Multi-Center Chart Audit Study

Administered By
Duke Cancer Institute
Awarded By
Incyte Corporation
Role
Principal Investigator
Start Date
End Date

Centers for Medical Countermeasures against Radiation Consortium

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Clinical Validation and Supply of SRI Radiation Biodosimeter

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
SRI International
Role
Principal Investigator
Start Date
End Date

RITN Opportunity for Radiological Preparedness

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Marrow Donor Program
Role
Principal Investigator
Start Date
End Date

2-O, 3-O desulfated heparin for the prevention of GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Cantex Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

Haploidentical vs sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia.

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.
Authors
Wieduwilt, MJ; Metheny, L; Zhang, M-J; Wang, H-L; Estrada-Merly, N; Marks, DI; Al-Homsi, AS; Muffly, L; Chao, N; Rizzieri, D; Gale, RP; Gadalla, SM; Cairo, M; Mussetti, A; Gore, S; Bhatt, VR; Patel, SS; Michelis, FV; Inamoto, Y; Badawy, SM; Copelan, E; Palmisiano, N; Kharfan-Dabaja, MA; Lazarus, HM; Ganguly, S; Bredeson, C; Diaz Perez, MA; Cassaday, R; Savani, BN; Ballen, K; Martino, R; Wirk, B; Bacher, U; Aljurf, M; Bashey, A; Murthy, HS; Yared, JA; Aldoss, I; Farhadfar, N; Liu, H; Abdel-Azim, H; Waller, EK; Solh, M; Seftel, MD; van der Poel, M; Grunwald, MR; Liesveld, JL; Kamble, RT; McGuirk, J; Munker, R; Cahn, J-Y; Lee, JW; Freytes, CO; Krem, MM; Winestone, LE; Gergis, U; Nathan, S; Olsson, RF; Verdonck, LF; Sharma, A; Ringdén, O; Friend, BD; Cerny, J; Choe, H; Chhabra, S; Nishihori, T; Seo, S; George, B; Baxter-Lowe, LA; Hildebrandt, GC; de Lima, M; Litzow, M; Kebriaei, P; Hourigan, CS; Abid, MB; Weisdorf, DJ; Saber, W
MLA Citation
Wieduwilt, Matthew J., et al. “Haploidentical vs sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia.Blood Adv, vol. 6, no. 1, Jan. 2022, pp. 339–57. Pubmed, doi:10.1182/bloodadvances.2021004916.
URI
https://scholars.duke.edu/individual/pub1497161
PMID
34547770
Source
pubmed
Published In
Blood Adv
Volume
6
Published Date
Start Page
339
End Page
357
DOI
10.1182/bloodadvances.2021004916

Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft-Versus-Host Disease While Preserving Graft-Versus-Leukemia Effect.

Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors. Importantly, previous studies have not evaluated whether graft-versus-leukemia (GVL) activity is preserved in donor T cells deficient for glycolysis. As a critical component affecting the clinical outcome, it is necessary to assess the anti-tumor activity following treatment with metabolic modulators in preclinical models. In the present study, we utilized T cells selectively deficient for glucose transporter 1 (Glut1T-KO), to examine the role of glycolysis exclusively in alloreactive T cells without off-targeting effects from antigen presenting cells and other cell types that are dependent on glycolysis. We demonstrated that transfer of Glut1T-KO T cells significantly improved acute GVHD outcomes through increased apoptotic rates, impaired expansion, and decreased proinflammatory cytokine production. In addition to impaired GVHD development, donor Glut1T-KO T cells mediated sufficient GVL activity to protect recipients from tumor development. A clinically relevant approach using donor T cells treated with a small molecule inhibitor of glycolysis, 2-Deoxy-D-glucose ex vivo, further demonstrated protection from tumor development. These findings indicate that treatment with glycolysis inhibitors prior to transplantation selectively eliminates alloreactive T cells, but spares non-alloreactive T cells including those that protect against tumor growth. The present study has established a definitive role for glycolysis in acute GVHD and demonstrated that acute GVHD can be selectively prevented through targeting glycolysis.
Authors
Huang, Y; Zou, Y; Jiao, Y; Shi, P; Nie, X; Huang, W; Xiong, C; Choi, M; Huang, C; Macintyre, AN; Nichols, A; Li, F; Li, C-Y; MacIver, NJ; Cardona, DM; Brennan, TV; Li, Z; Chao, NJ; Rathmell, JC; Chen, BJ
MLA Citation
Huang, Ying, et al. “Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft-Versus-Host Disease While Preserving Graft-Versus-Leukemia Effect.Front Immunol, vol. 13, 2022, p. 751296. Pubmed, doi:10.3389/fimmu.2022.751296.
URI
https://scholars.duke.edu/individual/pub1512762
PMID
35296079
Source
pubmed
Published In
Frontiers in Immunology
Volume
13
Published Date
Start Page
751296
DOI
10.3389/fimmu.2022.751296

Financial incentives to increase stool collection rates for microbiome studies in adult bone marrow transplant patients.

INTRODUCTION: In order to study the role of the microbiome in hematopoietic stem cell transplantation (HCT), researchers collect stool samples from patients at various time points throughout HCT. However, stool collection requires active subject participation and may be limited by patient reluctance to handling stool. METHODS: We performed a prospective study on the impact of financial incentives on stool collection rates. The intervention group consisted of allogeneic HCT patients from 05/2017-05/2018 who were compensated with a $10 gas gift card for each stool sample. The intervention group was compared to a historical control group of allogeneic HCT patients from 11/2016-05/2017 who provided stool samples before the incentive was implemented. To control for possible changes in collections over time, we also compared a contemporaneous control group of autologous HCT patients from 05/2017-05/2018 with a historical control group of autologous HCT patients from 11/2016-05/2017; neither autologous HCT group was compensated. The collection rate was defined as the number of samples provided divided by the number of time points we attempted to obtain stool. RESULTS: There were 35 allogeneic HCT patients in the intervention group, 19 allogeneic HCT patients in the historical control group, 142 autologous HCT patients in the contemporaneous control group (that did not receive a financial incentive), and 75 autologous HCT patients in the historical control group. Allogeneic HCT patients in the intervention group had significantly higher average overall collection rates when compared to the historical control group allogeneic HCT patients (80% vs 37%, p<0.0001). There were no significant differences in overall average collection rates between the autologous HCT patients in the contemporaneous control and historical control groups (36% vs 32%, p = 0.2760). CONCLUSION: Our results demonstrate that a modest incentive can significantly increase collection rates. These results may help to inform the design of future studies involving stool collection.
Authors
Thompson, JC; Ren, Y; Romero, K; Lew, M; Bush, AT; Messina, JA; Jung, S-H; Siamakpour-Reihani, S; Miller, J; Jenq, RR; Peled, JU; van den Brink, MRM; Chao, NJ; Shrime, MG; Sung, AD
MLA Citation
Thompson, Jillian C., et al. “Financial incentives to increase stool collection rates for microbiome studies in adult bone marrow transplant patients.Plos One, vol. 17, no. 5, 2022, p. e0267974. Pubmed, doi:10.1371/journal.pone.0267974.
URI
https://scholars.duke.edu/individual/pub1520468
PMID
35507633
Source
pubmed
Published In
Plos One
Volume
17
Published Date
Start Page
e0267974
DOI
10.1371/journal.pone.0267974

Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia.

Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated with overall survival (OS) and clinical outcomes. We hypothesized that circulating metabolic, inflammatory, and immune molecules have potential as predictive biomarkers for AML patients who receive HCT treatment. This retrospective study was designed with an exploratory approach to comprehensively characterize immune, inflammatory, and metabolomic biomarkers. We identified patients with AML who underwent HCT and had existing baseline plasma samples. Using those samples (n = 34), we studied 65 blood based metabolomic and 61 immune/inflammatory related biomarkers, comparing patients with either long-term OS (≥ 3 years) or short-term OS (OS ≤ 1 years). We also compared the immune/inflammatory response and metabolomic biomarkers in younger vs. older AML patients (≤30 years vs. ≥ 55 years old). In addition, the biomarker profiles were analyzed for their association with clinical outcomes, namely OS, chronic graft versus host disease (cGVHD), acute graft versus host disease (aGVHD), infection and relapse. Several baseline biomarkers were elevated in older versus younger patients, and baseline levels were lower for three markers (IL13, SAA, CRP) in patients with OS ≥ 3 years. We also identified immune/inflammatory response markers associated with aGVHD (IL-9, Eotaxin-3), cGVHD (Flt-1), infection (D-dimer), or relapse (IL-17D, bFGF, Eotaxin-3). Evaluation of metabolic markers demonstrated higher baseline levels of medium- and long-chain acylcarnitines (AC) in older patients, association with aGVHD (lactate, long-chain AC), and cGVHD (medium-chain AC). These differentially expressed profiles merit further evaluation as predictive biomarkers.
Authors
Siamakpour-Reihani, S; Cao, F; Lyu, J; Ren, Y; Nixon, AB; Xie, J; Bush, AT; Starr, MD; Bain, JR; Muehlbauer, MJ; Ilkayeva, O; Byers Kraus, V; Huebner, JL; Chao, NJ; Sung, AD
MLA Citation
Siamakpour-Reihani, Sharareh, et al. “Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia.Plos One, vol. 17, no. 6, 2022, p. e0268963. Pubmed, doi:10.1371/journal.pone.0268963.
URI
https://scholars.duke.edu/individual/pub1524447
PMID
35700185
Source
pubmed
Published In
Plos One
Volume
17
Published Date
Start Page
e0268963
DOI
10.1371/journal.pone.0268963

The importance of endothelial protection: the emerging role of defibrotide in reversing endothelial injury and its sequelae.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potentially life-threatening complication of hematopoietic cell transplantation (HCT), results from prolonged sinusoidal endothelial cell activation and profound endothelial cell damage, with sequelae. Defibrotide, the only drug approved in the United States and Europe for treating VOD/SOS post-HCT, has European Commission orphan drug designation for preventing graft-versus-host disease (GvHD), associated with endothelial dysfunction. This endothelial cell protector and stabilizing agent restores thrombo-fibrinolytic balance and preserves endothelial homeostasis through antithrombotic, fibrinolytic, anti-inflammatory, anti-oxidative, and anti-adhesive activity. Defibrotide also preserves endothelial cell structure by inhibiting heparanase activity. Evidence suggests that downregulating p38 mitogen-activated protein kinase (MAPK) and histone deacetylases (HDACs) is key to defibrotide's endothelial protective effects; phosphatidylinositol 3-kinase/Akt (PI3K/AKT) potentially links defibrotide interaction with the endothelial cell membrane and downstream effects. Despite defibrotide's being most extensively studied in VOD/SOS, emerging preclinical and clinical data support defibrotide for treating or preventing other conditions driven by endothelial cell activation, dysfunction, and/or damage, such as GvHD, transplant-associated thrombotic microangiopathy, or chimeric antigen receptor T-cell (CAR-T) therapy-associated neurotoxicity, underpinned by cytokine release syndrome and endotheliitis. Further preclinical and clinical studies will explore defibrotide's potential utility in a broader range of disorders resulting from endothelial cell activation and dysfunction.
Authors
Richardson, PG; Palomo, M; Kernan, NA; Hildebrandt, GC; Chao, N; Carreras, E
MLA Citation
Richardson, Paul G., et al. “The importance of endothelial protection: the emerging role of defibrotide in reversing endothelial injury and its sequelae.Bone Marrow Transplantation, vol. 56, no. 12, Dec. 2021, pp. 2889–96. Epmc, doi:10.1038/s41409-021-01383-x.
URI
https://scholars.duke.edu/individual/pub1516152
PMID
34584241
Source
epmc
Published In
Bone Marrow Transplantation
Volume
56
Published Date
Start Page
2889
End Page
2896
DOI
10.1038/s41409-021-01383-x