Overview

Graft-versus-host disease (GVHD) is one of the leading causes of morbidity and mortality following hematopoietic stem cell transplantation. Our group focuses on understanding the mechanisms driving GVHD and developing new approaches to prevent the disease. We recently completed a phase 2 clinical trial evaluating T cell costimulation blockade with abatacept in the prevention of GVHD (ABA2). The addition of abatacept resulted in a striking reduction in GVHD leading to a statistically significant improvement in overall survival in patients undergoing unrelated donor transplant for hematologic malignancies. The impressive results of this study have led to a Breakthrough Therapy Designation by the FDA and we are currently pursuing and FDA indication for abatacept in the prevention of GVHD. If successful it would be the first drug to be FDA approved for GVHD prevention. We currently have an ongoing phase 2 trial evaluating abatacept in the prevention of GVHD in patients with non-malignant disease (ASCENT) and will soon open another phase 2 trial evaluating extending dosing abatacept (ABA3).

One of the major barriers to the prevention and treatment of GVHD is a poor understanding of the mechanisms driving the disease. Our group uses longitudinal immune profiling through flow cytometry and RNAseq to identify the pathways involved in the development of GVHD. The overall goal is to identify biomarkers of GVHD that are present before the appearance of the clinical symptoms so that prevention and treatment can be modified accordingly.

Sharmila Raghunandan, MD, Fellow, Pediatric Hematology/Oncology

Education: BS, Macalester College; MS, University of Minnesota; MD, University of New England College of Osteopathic Medicine; Residency, University of Minnesota; Fellowship, Emory University

Current Project: Subanalysis of ABA2 Pediatric Outcomes. Primary fellow on the phase 2 trial: Acute GVHD Suppression using Costimulation Blockade to Expand Non-malignant Transplant (ASCENT)

Fun Fact: Grew up in Bangalore, India and Muscat, Oman before I decided to move to the Twin Cities, Minnesota for college.

Email: sraghu2@emory.edu

 

 

Yvonne Suessmuth, PhD

Education: BSc (Biomedical Science), The Robert Gordon University, BSc (Biology), Bonn-Rhein-Seig University of Applied Sciences; PhD (Molecular Immunology), Queen’s University

Current Project: Immune phenotyping in GVHD patients after hematopoietic stem cell transplant

Fun Fact: I lived in Belfast, Northern Ireland for six years. I also love to read and craft.

Email: ysuessm@emory.edu

Watkins BK, Qayed M, McCraken C, Bratrude B, Betz K, Suessmuth Y, Yu A, Sinclair S, Furlan S, Bosinger S, Tkachev V, Rhodes J, Tumlin A, Narayan A, Cribbin, K, Gillespie S, Gooley T, Pasquini M, Hebert K, Kapoor U, Rogatko A, Tighiouart M, Kim S, Bresee C, Choi S, Davis J, Duncan C, Giller R, Grimley M, Harris A, Jacobsohn D, Lalefar N, Norkin M, Farhadfar N, Pulsipher M, Shenoy S, Petrovic A, Shultz K, Yanik G, Waller E, Levine J, Ferrara J, Blazar B, Langston A, Horan J, Kean LS. A phase 2 trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021 Jan 15:JCO.20.01086. doi:10.1200/JCO.20.01086. Epub ahead of print. PMID: 33449816.

 

Tkachev V, Kaminski J, Potter E, Furlan S, Yu A, Hunt D, McGuckin C, Zheng H, Colonna L, Gerdemann U, Carlson J, Hoffman M, Olvera J, English C, Baldessari A, Panoskaltsis-Mortari A, Watkins BK, Qayed M, Suessmuth Y, Betz K, Bratrude B, Langston A, Horan J, Ordovas-Montanes J, Shalek A, Blazar B, Roederer M, Kean LS. Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive resident memory T cell states. Sci Trans Med. 2021 Jan13;13(576): eabc0227. PMID: 33441422.

 

Watkins B, Tkachev V, Furlan S, Hunt D, Betz K, Yu A, Brown M, Poirier N, Zheng H, Taraseviciute A, Colonna L, Mary C, Blancho G, Soulillou J, Panoskaltsis-Mortari A, Sharma P, Garcia A, Stroert E, Hamby K, Garrett A, Deane T, Blazar B, Vanhove B, Kean L. Systems analysis of CD28 versus CD80/86 blockade for GVHD prevention. J.Clin Invest. 2018 Aug 31; 128(9):3991-4007. PubMed PMID: 30102255.

 

Tkachev V, Furlan SN, Watkins B, Hunt DJ, Zheng HB, Panoskaltsis-Mortari A, Betz K, Brown M, Schell JB, Zeleski K, Yu A, Kirby I, Cooley S, Miller JS, Blazar BR, Casson D, Bland-Ward P, Kean LS. Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant. Sci Transl Med. 2017 Sep 20;9(408). PubMed PMID: 28931653.

 

Watkins B, Horan J, Storer B, Martin PJ, Carpenter PA, Flowers ME. Recipient and donor age impact the risk of developing chronic GVHD in children after allogeneic hematopoietic transplant. Bone Marrow Transplant. 2017; 52(4):625-626.

 

Hippen KL, Watkins B, Tkachev V, Lemire AM, Lehnen C, Riddle MJ, Singh K, Panoskaltsis-Mortari A, Vanhove B, Tolar J, Kean LS, Blazar BR. Preclinical testing of anti-human CD28 Fab' antibody in a novel nonhuman primate (NHP) small animal rodent model of xenogenic graft-versus-host disease (GVHD). Transplantation. 2016 Dec: 100(12):2630-2639. PubMed PMID: 27607527.

 

Furlan S*, Watkins B*, Tkachev V, Cooley S, Panoskaltsis-Mortari A, Betz K, Brown M, Hunt D, Schell J, Zeleski K, Yu A, Giver C, Waller E, Miller J, Blazar B, Kean LS. Systems Analysis Uncovers Inflammatory Th/Tc17-Driven Modules During Acute GVHD in Monkey and Man. Blood. 2016 Nov 24; 128(21):2568-2579. PubMed PMID:27758873.

 

Suessmuth, Y, Mukherjee R, Watkins B, Koura D, Finstermeier K, Desmarais C, Stempora L, Horan J; Langston A, Qayed M, Khoury HJ, Grizzle A, Cheeseman JA, Conger JA, Robertson J, Garrett A, Kirk A; Waller EK, Blazar BR, Mehta AK,  Robins AS, Kean LS. CMV Reactivation Drives Post-Transplant T Cell Reconstitution and Results in Defects in The Underlying TCRb Repertoire. Blood. 2015 Jun 18;125(25):3835-50. PubMed PMID: 25852054.

 

Furlan S, Watkins B, Flynn R, Tkachev V, Flynn R, Cooley S, Ramakrishnan S, Singh K, Giver C, Hamby K, Stempora L, Garrett A, Chen J, Betz K, Ziegler C, Tharp G, Bosinger S, Promislow D, Miller J, Waller E, Blazar B, Kean LS. Defining the Molecular Signature of Acute GVHD: Transcriptome Analysis Reveals Novel Targetable Pathways for Disease Prevention. Sci Transl Med. 2015 Nov 25;7(315):315ra191. PubMed PMID: 26606970.

 

Zheng HB*, Watkins B*, Tkachev V, Yu S, Tran D, Furlan S, Zeleski K, Singh K, Hamby K, Hotchkiss C, Lane J, Gumber S, Adams AB, Cendales L, Kirk AD, Kaur A, Blazar BR, Larsen CP, Kean LS. The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016 Aug 8. Epub ahead of print. PubMed PMID: 27500470.

 

Kaliyaperumal S, Watkins B, Sharma P, Furlan S, Ramakrishnan S, Giver C, Garcia A, Courney C, Knight H, Strobert E, Elder E, Crenshaw T, Blazar B, Waller E, Westmoreland S, Kean LS. CD8-Predominant T-cell CNS infiltration accompanies GVHD in primates and is improved with immunoprophylaxis. Blood. 2014 Mar 20;123(12):1967-9. PubMed PMID: 24652969.

 

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NIH/NHLBI: K23 HL136900

Characterizing the molecular signature of chronic graft-versus-host disease.

PI: Watkins