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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1797-1808.
Prepublished online as a Blood First Edition Paper on June 1, 2006; DOI 10.1182/blood-2006-02-001909.
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PLENARY PAPERS
Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation
Persis J. Amrolia,
Giada Muccioli-Casadei,
Helen Huls,
Stuart Adams,
April Durett,
Adrian Gee,
Eric Yvon,
Heidi Weiss,
Mark Cobbold,
H. Bobby Gaspar,
Cliona Rooney,
Ingrid Kuehnle,
Victor Ghetie,
John Schindler,
Robert Krance,
Helen E. Heslop,
Paul Veys,
Ellen Vitetta, and
Malcolm K. Brenner
From the Departments of Bone Marrow Transplantation and Immunology, Great Ormond St Childrens Hospital, London, United Kingdom; Cancer Immunobiology Center, University of Texas Southwestern Medical School, Dallas, TX; Cancer Research United Kingdom (CRUK) Institute for Cancer Studies, University of Birmingham, United Kingdom; CEINGE Biotechnologie Avanzale and Dipartimento di Biochimica e Biotecnologie Medicine, University Federico II di Napoli, Italy; and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX.
Poor T lymphocyte reconstitution limits the use of haploidentical stem cell transplantation (SCT) because it results in a high mortality from viral infections. One approach to overcome this problem is to infuse donor T cells from which alloreactive lymphocytes have been selectively depleted, but the immunologic benefit of this approach is unknown. We have used an anti-CD25 immunotoxin to deplete alloreactive lymphocytes and have compared immune reconstitution after allodepleted donor T cells were infused at 2 dose levels into recipients of T-cell–depleted haploidentical SCT. Eight patients were treated at 104 cells/kg/dose, and 8 patients received 105 cells/kg/dose. Patients receiving 105 cells/kg/dose showed significantly improved T-cell recovery at 3, 4, and 5 months after SCT compared with those receiving 104 cells/kg/dose (P < .05). Accelerated T-cell recovery occurred as a result of expansion of the effector memory (CD45RA–CCR-7-) population (P < .05), suggesting that protective T-cell responses are likely to be long lived. T-cell–receptor signal joint excision circles (TRECs) were not detected in reconstituting T cells in dose-level 2 patients, indicating they are likely to be derived from the infused allodepleted cells. Spectratyping of the T cells at 4 months demonstrated a polyclonal V repertoire. Using tetramer and enzyme-linked immunospot (ELISPOT) assays, we have observed cytomegalovirus (CMV)– and Epstein-Barr virus (EBV)–specific responses in 4 of 6 evaluable patients at dose level 2 as early as 2 to 4 months after transplantation, whereas such responses were not observed until 6 to 12 months in dose-level 1 patients. The incidence of significant acute (2 of 16) and chronic graft-versus-host disease (GVHD; 2 of 15) was low. These data demonstrate that allodepleted donor T cells can be safely used to improve T-cell recovery after haploidentical SCT and may broaden the applicability of this approach.
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