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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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Submitted February 6, 2006
Accepted May 15, 2006
Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplant
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
Great Ormond St Children's Hospital, London, UK
University Federico II di Napoli, Italy
Baylor College of Medicine, Houston, USA
University of Birmingham, Birmingham, UK
University of Texas Southwestern Medical School, Dallas, USA
* Corresponding author; email: amrolp1{at}gosh.nhs.uk.
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 immunological 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 post-SCT compared with those receiving 104 cells/kg/dose (p< 0.05). Accelerated T-cell recovery occurred as a result of expansion of the effector memory (CD45RA-CCR-7-) population (p< 0.05), suggesting that protective T-cell responses are likely to be long-lived. 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 Vb repertoire. Using tetramer and ELISPOT assays, we have observed CMV and EBV-specific responses in 4/6 evaluable patients at dose level 2 as early as 2-4 months post-transplant, whereas such responses were not observed until 6-12 months in dose level 1 patients. The incidence of significant acute (2/16) and chronic GVHD (2/15) 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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