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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4023.
T-cell therapy for viral and fungal infectionsMEDIZINISCHE KLINIK AND POLIKLINIKII, BAYERISCHE JULIUS-MAXIMILIANS UNIVERSITY WUERZBURG
Perruccio and colleagues demonstrate feasibility and efficacy of adoptive immunotherapy with donor-derived T-cell clones in controlling viral and fungal infection following haploidentical stem cell transplantation.
Transplantation of hematopoietic stem cells from full HLA haplotype-mismatched (haploidentical) family donors is an option for these patients but requires extensive T-cell depletion of the graft, leading to a delayed immune reconstitution following transplantation. Thus, after haploidentical transplantation, patients are at very high risk of developing severe infectious complications. Adoptive transfer of donor-derived virus-specific CD8+ T cells has been shown to be safe and effective in prophylaxis and treatment of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection following stem cell transplantation from an HLA-identical related and unrelated donor.1-3 Due to the high degree of mismatching between donor and patient in haploidentical transplantation, transfer of donor T cells to improve immune reconstitution in these patients is associated with a high risk of severe acute graft-versus-host disease (GvHD). But immunotherapy with highly enriched polyclonal virus-specific CD4+ T cells has been reported to be safe and effective in a small cohort of patients, including one recipient of a haploidentical transplant.4 Here, Perruccio and colleagues report the safe and effective transfer of donor-derived pathogen-specific T cells to recipients of a haploidentical transplant. There are 2 important messages. No infusion-related toxicity nor induction of GvHD were reported in any of the previous studies using adoptive transfer of donor-derived T cells and even more important in none of the 35 recipients of a haploidentical transplant in the study by Perruccio et al when less than 106 donor CD4+ T cells/m2 were transferred. Thus, transfer of highly enriched pathogen-specific T cells even from haploidentical donors is safe. In spite of the fact that only a small number of pathogen-specific T cells was administered, specific T-cell responses could be detected in most of the patients in the previous studies and all patients in the trial reported here. All of the patients in this study showed a surprisingly prompt increase in CD4+ as well as CD8+ T-cell responses to CMV as soon as 3 weeks after transfer. Obviously, even extensively in vitro–cultured T cells were able to rapidly expand in vivo when administered to lymphopenic patients not receiving immunosuppressive medication for GvHD prophylaxis. When compared with a control group, patients receiving CMV-directed immunotherapy had a lower risk of CMV reactivation and disease. It has been shown before that patients with Aspergillus-specific T helper 1 (Th1) responses have a better chance to survive invasive aspergillosis.5 But this is the first study that describes adoptive T-cell therapy not only for viral but also for invasive fungal infection. Aspergillus-directed CD4+ Th1 responses were detected in all recipients as soon as 3 weeks after the transfer, and 9 of 10 treated patients showed a decrease in their galactomannan antigenemia and resolution of pulmonary infiltrates. Thus, Perruccio and colleagues for the first time also document antifungal efficacy of T-cell therapy.
There are several issues to be resolved before adoptive transfer of pathogen-specific T cells will become routine therapy in recipients of an allogeneic stem cell graft. First, more efficient culture and stimulation techniques or improved selection devices are needed to reduce long-term in vitro culture and to allow enrichment of pathogen-specific T cells under GMP (Good Medical Practice) conditions. Only then will it be possible to conduct clinical trials with highly enriched pathogenspecific T cells that contain not only terminally differentiated effector cells, but also central memory T cells, which are essential to build up a memory T-cell response in the recipient. If so, adoptive immunotherapy will be increasingly used to prevent or control various infectious complications after transplantation. References
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