T cells to go

The adoptive transfer of T cells specific for viral or tumor-associated antigens has been shown to be a promising form of immunotherapy in animal models and several “proof of principal” clinical studies. The major difficulties identified to date relate to limitations in the widespread ability to rapidly generate adequate numbers of antigen-specific T cells, as well as the capacity of such populations to persist and expand following in vivo transfer until their target antigen is eliminated and/or endogenous immunologic memory is established.

Szmania and colleagues (page 505) report on their experience with a strategy to circumvent this first limitation. Targeting the problem of CMV reactivation in allogeneic BMT recipients, these authors studied the ability to rapidly expand CD8⁺ T cells specific for a dominant HLA-A*0201–restricted epitope of CMV pp65 matrix protein. Starting with 200 mL of peripheral blood from healthy donors, monocyte-derived dendritic cells pulsed with pp65 peptide were used to amplify antigen-specific CTL from purified CD8⁺ T cells. After 2 rounds of stimulation, HLA-A*0201 tetramers loaded with pp65 peptide were used to enrich CMV-specific CTL. This relatively CMV-specific, polyclonal population was then expanded for an additional 10 days using both antigen-specific and nonspecific stimulation, resulting in sufficient numbers of cells for adoptive transfer.

The resulting population lysed CMV-sensitized targets and had a restricted (but oligoclonal) pattern of T-cell–receptor utilization. Importantly, the authors point out that, given adequate availability of HLA-tetramer, the final amplification step (which loses some specificity) might not even be necessary. A major concern of adoptive immunotherapy unique to the allogeneic BMT setting is the inadvertent transfer of allospecific T cells, which greatly increases the risk of GVHD, especially in the early posttransplantation period when risk of CMV reactivation is greatest. Indeed, the use of this strategy in the haploidentical (ie, haplomismatched) setting, which is proposed here, runs the additional risk of HLA-*A0201–restricted CMV-specific T cells recognizing allogeneic HLA molecules presenting self peptide (“self MHC + X = allo MHC + Y”).

Ultimately, the relative safety and efficacy of this approach as applied to CMV will need to be compared to pharmacologic therapies. Whatever the outcome in this setting, however, the continuously improving ability to rapidly expand antigen-specific T cells for therapy is an enabling technology sure to impact on clinical medicine.