Functional characterization of alloreactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allodepletion strategy

Author:

Samarasinghe Sujith1,Mancao Christoph1,Pule Martin2,Nawroly Niga3,Karlsson Helen1,Brewin Jennifer1,Openshaw Peter3,Gaspar H. Bobby1,Veys Paul4,Amrolia Persis J.14

Affiliation:

1. Department of Molecular Immunology, Institute of Child Health, London;

2. Department of Haematology, University College Hospital, London;

3. National Heart and Lung Institute, St Mary's Hospital, Imperial College, London;

4. Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom

Abstract

AbstractImmunotherapy with allodepleted donor T cells (ADTs) improves immunity after T cell–depleted stem cell transplantation, but infection/relapse remain problematic. To refine this approach, we characterized the expression of surface markers/cytokines on proliferating alloreactive T cells (ATs). CD25 was expressed on 83% of carboxyfluorescein diacetate succinimidyl esterdim ATs, confirming this as an excellent target for allodepletion. Seventy percent of CD25− ATs expressed CD71 (transferrin receptor), identifying this as a novel marker to target ATs persisting after CD25 depletion. Comparison of residual alloreactivity after combined CD25/71 versus CD25 immunomagnetic depletion showed enhanced depletion of alloreactivity to host with CD25/71 depletion in both secondary (2°) mixed lymphocyte reactions (P < .01) and interferon-γ enzyme-linked immunospot assays (P < .05) with no effect on third-party responses. In pentamer/interferon-γ enzyme-linked immunospot assays, antiviral responses to cytomegalovirus, Epstein-Barr virus, and adenovirus were preserved after CD25/71 allodepletion. CD25/71 ADTs can be redirected to recognize leukemic targets through lentiviral transfer of a chimeric anti-CD19ζ T-cell receptor. Finally, we have established conditions for clinically applicable CD25/71 allodepletion under European Union Good Manufacturing Practice conditions, resulting in highly effective, reproducible, and selective depletion of ATs (median residual alloreactivity to host in 2° mixed lymphocyte reaction of 0.39% vs third-party response of 62%, n = 5). This strategy enables further clinical studies of adoptive immunotherapy with larger doses of ADTs to enhance immune reconstitution after T cell-depleted stem cell transplantation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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