Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 155

To further enhance the specificity of T cells for TAA, chimeric antigen recep-
tors (CARs) have been developed and tested clinically, primarily in the set-
ting of CD19, which is constitutively expressed on most B-cell malignancies.
CARs are composed of an antigen recognition domain of a specific antibody
that is fused with the intracellular domain of the CD3-zeta chain or FCγRI
protein. CD19 CAR-modified T cells were shown to be safe and efficacious in
patients with lymphoid malignancies [94] . In order to enhance the efficacy
of CD19 CAR-modified T cells, costimulatory molecule receptors have been
added to CAR-modified T cells in order to provide costimulatory signals to
enhance the potency of the immune response. In one report, Brentjens et al.
replaced the inert CD8 transmembrane domain of CD19 CAR-modified T
cells with the cytoplasmic signaling domains of the T-cell costimulatory
CD28 receptor, and subsequently administered cells to patients with CLL
and ALL [95] . The infused cells demonstrated rapid trafficking to the tumor
site and retained cytotoxic activities. In addition, clinical responses were
seen in some patients. In a similar approach, Porter et al. introduced the
CD137 costimulatory receptor and the CD3-zeta signal-transduction com-
ponent of the T-cell antigen receptor to CD19 CAR-modified T cells [96] .
Cells were infused into patients with CLL and were shown to persist at high
levels for 6 months in the blood and bone marrow in one patient who dem-
onstrated a loss in CD19 expressing normal and leukemic cells. Because of
the difficulties in generating antibodies against peptide/HLA complexes,
primarily due to the fact that most HLA peptides make up a small compo-
nent (9-14 amino acids) of the peptide/HLA-complex, to date there are no
CARs that target peptide/HLA complexes. However, since antibodies target-
ing PR1/HLA-A2 and WT1/HLA-A2 have been generated, this technology
may soon be applied to these TAAs.

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Healthy donor vaccination

Another approach to generating TAA-specific CTL involves vaccinating
healthy donors with a peptide vaccine prior to collecting the T-cell graft,
hence providing a donor graft that is enriched with CTL that targets a spe-
cific TAA. This methodology was recently demonstrated in a mouse model
using WT1 antigen. In that model, allo-HSCT from vaccinated healthy
MHC-matched mice eradicated established leukemia in allogeneic, but not
syngeneic, recipients [97] . Although these data are promising, this approach
has yet to be tried in humans in view of the logistic and ethical dilemmas
that may be encountered.

Unanswered questions

Despite the demonstrated success of targeting TAA in solid and hemato-
logical malignancies, there are numerous questions that must be ade-
quately answered for these therapies to become part of the standard of care
approach to cancer treatment. One of the biggest dilemmas in targeting TAA
is the off-target toxicity that is seen, despite the specificity of the TAA for
the malignant tissue. One example was the loss of normal B cells in a CLL
patient that received CD19 CAR [96] . Although this side effect was a tran-
sient and predictable immune response against normal tissue, oftentimes
it is difficult to predict autoimmunity following vaccines. Furthermore, the