Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

“…Six patients are alive (nos. 1,6,7,8,10,11) at a median of 476 days after transplant (range, 278-674 days) ( Table 1).…”

“…[4][5][6] Consequently, efforts have been made to retain the desired T-cell subsets while selectively depleting alloreactive T cells [7][8][9] or enriching for the cells that are directed to pathogens or malignancies, or that are enriched for GVHD-suppressive regulatory T cells. [10][11][12] Although each of these strategies is feasible, it is difficult to develop a single T-cell manipulation that both eliminates alloreactivity and spares T cells representing all the available antiviral and antitumor specificities in the donor's peripheral blood (PB).…”

Cellular therapy with sequential unmanipulated donor lymphocyte infusions in drug-resistant cytomegalovirus (CMV) encephalitis

“…1 Viral load was reduced or cleared in 15 patients (83%) without graft-versus-host disease (GVHD) induction. Despite the encouraging results reported in this and previous studies, [1][2][3][4][5][6] the clinical use of CMV-specific T-cell adoptive immunotherapy (CMV-TC) has been limited to a few transplant centers where the transplantation volume and the incidence of CMV disease are high enough and the cell-processing facilities technically advanced enough to justify developing an adoptive antiviral immunotherapy program. The time taken to prepare patientspecific products and the lack of virus-specific T cells in cord blood and seronegative donors also restricts application.…”

Progress and prospects: graft-versus-host disease

“…The successful clinical results obtained with these approaches were counterbalanced by intrinsic limitations of the T-cell repertoire infused, which were insufficient to cope with the wide range of pathogens that threaten immunodeficient patients. Recently, Leen et al 27 showed that it is possible to simultaneously isolate and expand bivirus-or trivirusspecific donor T lymphocytes targeting EBV, CMV and adenovirus, by stimulating donor cells with autologous monocytes and EBV cell lines infected with a recombinant adenovirus encoding a CMV structural protein. The genetic modification of antigen-presenting cells to express viral antigens stimulates the expansion of T lymphocytes specific for multiple viruses, thus promoting the generation of a multifunctional T-cell repertoire from a single cell culture.…”

“…When infused to transplanted patients, bivirus-specific T-cell lines promoted clinically measurable antiviral activity in the absence of GvHD. 27 Several advances were made to reduce the time required for the generation of multiviral-specific lymphocytes, 28 and additional viral antigens can be included into the system, thus providing a wider repertoire. Theoretically, the same approach could be pursued to boost GvT, while providing high-avidity tumorspecific lymphocytes, or lymphocytes directed to minor histocompatibility antigens, selectively expressed in the hematopoietic tissue.…”