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that promotes apoptosis only in cells with the transfected gene can be
administered. This technology has been used safely in over 120 transplant
patients with the herpes simplex thymidine kinase gene as the suicide vehi-
cle. Importantly, all cases of GVHD that developed were adequately con-
trolled, a majority through the activation of the thymidine kinase pathway
alone (reviewed in
[69]
). Thymidine kinase polyclonal T cells also persisted
for an extended period of time
in vivo,
unlike transferred populations first
expanded
in vitro,
and therefore could contribute to improved immune
reconstitution.
A similar additional strategy was recently reported, using a modified human
FK-binding protein fused to caspase 9 to form an inducible “safety switch”
[70]
. This genetic switch was then transfected into a population of poly-
clonal T cells that had first been depleted of highly alloreactive cells. Fol-
lowing haploidentical transplant and infusion of “caspase 9” T cells, four
patients developed mild skin GVHD, one with simultaneous liver GVHD.
GVHD completely resolved in all four patients after a single dose of AP1903,
the activating biomolecule. Transfected cells were identified up to a year
after administration, and the triggering of the suicide gene did not affect
development of the nontransfected immune system.
502
The use of chimeric antigen receptors (CARs) to redirect T-cell reactivity
has also now achieved clinical reality. First-generation CARs consist of an
extracellular domain encoding a single-chain immunoglobulin specific for
tumor antigen, an immunoglobulin transmembrane region, and an intra-
cellular domain encoding the human CD3-ζ protein
[71]
. This CAR allows
for specific recognition of tumor antigens without the need for MHC pro-
cessing and presentation (see
Figure 21.2
).
First-generation CAR T cells possessed limited clinical efficacy because of
poor T-cell expansion. Second-generation CARs improved T-cell expansion
by incorporating a costimulatory signaling domain into the CD3-ζ por-
tion of the construct. Using CAR T cells specific for CD19, this approach
eradicated chemotherapy-refractory chronic lymphocytic leukemia (CLL)
in three patients
[72]
. Two of these patients experienced a complete remis-
sion of CLL for >10 months, with a partial remission in the third. Of note,
the CAR T cells expanded
in vivo
homed to the bone marrow, retained their
anti-CD19 reactivity over time, and developed into memory T cells.
Future approaches may be a hybrid of these strategies, combining CAR
T-cell specificity with a suicide safety switch, thereby allowing targeted
elimination of antigen-specific T cells at a defined time
[73]
. While gene-
modified cellular therapies require careful monitoring, the long-term con-
sequences of CAR T-cell persistence remain unknown, and CAR T cells may
cross-react with previously unappreciated antigens
[74]
. We believe these
therapies hold particular promise.
Conclusion
After 50 years, the risks of allogeneic BMT outweigh its potential benefits for
many patients. Recent advances have lowered these risks on multiple fronts,
including through better GVHD diagnosis and prognostication, improved
GVHD prophylaxis, additional anti-tumor immunotherapies, an improved
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