Blood, 1 August 2001, Vol. 98, No. 3, pp. 503-503
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.
Hyam Levitsky
Johns Hopkins University
