2. The concept that transfer of immunity from donor to recipient
following successful allogeneic transplantation is capable of
eradicating residual disease in the patient is one of the most
significant biologic findings with implications well beyond the
transplant setting.
This concept, now beyond dispute, was developed from
observations in a variety of clinical settings.
The first major observation came from rare instances where
patients with hematologic malignancies were transplanted
with Genetically Identical (Syngeneic) Donors.
3. The finding that such patients did not develop GVHD yet had
a higher incidence of disease relapse was a striking and
unexpected finding.
Larger numbers of patients revealed that the risk of
relapse was not only dependent on the remission status of
the patient, but also related to the underlying disease.
Patients with CML had the greatest allogeneic effect and a
significantly higher risk of relapse following syngeneic as
compared with HLA-matched allogeneic transplantation.
4. A significant impact, albeit to a lesser extent, was also
observed for patients with AML, whereas patients with ALL
had less of an allogeneic donor effect.
These observations led to the concept that not all
diseases were immunologically identical and that some
were well recognized whereas others were less well
recognized.
5. Further support for the allogeneic effect came from studies
of T cell depletion of the graft.
The motivation to perform T cell depletion was based on
the expectation that removal of donor-derived T cells
would reduce the risk of GVHD.
The finding that GVHD could be almost completely
eliminated by successful T cell depletion even in the
absence of immunosuppressive drugs was a major finding.
6. The later observation that these patients had a much higher
risk of disease recurrence as well as a higher incidence of
graft rejection was sobering.
These results linked GVHD with GVT, further supporting
the finding that patients who developed some degree of
GVHD, especially chronic GVHD, had a significantly
reduced risk of disease relapse, providing further
evidence for the GVT effect.
7. The final and definitive demonstration of a GVT effect came
from the application of DLIs.
The observation that patients who had undergone
allogeneic HCT and later relapsed could be rendered
back into remission, in some instances even a molecular
remission, by the simple application of donor-derived
lymphocytes was a thrilling finding.
The treatment of larger numbers of patients again
demonstrated variable responses, with some diseases, such
as CML, being very responsive, whereas others, such as
ALL, were less responsive.
Long-term followup of patients successfully treated with
DLI revealed that patients who respond, especially with a
molecular response, have remarkably durable remissions
8. These observations have definitively established the GVT
effect as a biologic entity capable of controlling an otherwise
lethal condition such as acute leukemia.
Despite these findings, the biologic basis for the GVT effect
remains relatively obscure.
The cells responsible for the GVT effect clearly include T
cells and there is emerging evidence that NK cells are
also responsible for tumor cell control, especially in some
special situations such as following haploidentical
transplantation.
9. A major question continues to be whether the T cells
resulting in GVHD are the same populations of cells as
those responsible for the GVT effect.
The structures recognized by the immune effector cells
have been proposed to be alloantigens, such as minor
histocompatibility antigens, unique structures on the
malignant cells, such as products of chromosomal
translocations, or other specific markers of the malignant
phenotype.
10. The demonstration of the GVT effect has led to the concept
that perhaps GVHD may be separable from GVT.
A variety of strategies have been proposed in an effort to
enhance the GVT effect while minimizing GVHD.
One approach has been to manipulate DLI to reduce the risk
of GVHD inherent in its use.
The depletion of CD8+ cells by immunomagnetic
techniques has resulted in a relatively low incidence of
GVHD.
11. The finding that some patients developed powerful disease
responses without GVHD has provided support that these
biologic reactions can be separated.
An alternative approach has been to introduce a suicide
gene into the donor lymphocytes such that they can be
eradicated should GVHD develop.
12. To enhance specificity, others have attempted to clone T
cells capable of recognizing the tumor cells but not normal
host cells such as fibroblasts or lymphoblastoid cells.
Tumor-reactive T cells have been developed and even used
clinically.
Although this approach is elegant, there are a number of
technical limitations.
An alternative strategy has been to use engineered
populations of effector cells capable of expansion ex vivo,
which have limited capacity for GVHD induction.
13. One such population of cells derived from T cells which upon
activation with the timed addition of interferon-, anti-CD3
monoclonal antibodies, and IL-2 result in the dramatic
expansion of effector cells, which share phenotypic and
functional properties of both T and NK cells.
These cells, termed cytokine-induced killer cells, have
biologic activity in a number of different animal models and
have a limited capacity for GVHD induction partly because of
the production of interferon-a.
Other groups have used NK cells, which have GVT activity
but a limited capacity for GVHD induction through as-yet-
unexplained mechanisms.
14. A variety of cytokines have been evaluated for their ability to
impact GVHD without limiting GVT reactions.
These studies are largely performed in animal model
systems with defined end points that serve as preclinical
models.
Cytokines, such as IL-2, keratinocyte growth factor, and
other interleukins such as IL-18, maintain or enhance GVT
while reducing GVHD.
Another strategy has been to use phenotypically defined
populations of T cells that have the capability to regulate
immune responses.
The best characterized population of such regulatory T (Treg)
cells are CD4+ T cells that coexpress the IL-2 a-receptor
CD25.
15. Adjusting the number of Treg cells within the graft has
resulted in the control of GVHD in murine models even
across major histocompatibility barriers.
More recent studies indicate that the combination of
defined numbers of conventional CD4+ and CD8+ T cells
with Treg cells resulted in control of GVHD with
maintenance of GVT reactions.
These exciting observations suggest that manipulation of the
graft could have a major impact on diverse biologic reactions
such as GVHD and GVT, which will be explored in future
clinical trials.
16. Yet another approach has been to attempt to manipulate the
immune environment of the recipient to raise the barrier
required for GVHD induction.
Studies discussed above in murine models have
demonstrated that the combination of total lymphoid
irradiation with anti-T cell antiserum dramatically alters the
immune environment of the recipient such that up to 1000
times the number of donor-derived T cells can be infused
without induction of GVHD.
17. One possible unifying mechanism to explain these
experimental results is that for GVHD to develop,
alloreactive T cells must be present capable of activation
and proliferation in response to recipient alloantigens.
Conversely, GVT also requires T cell activation yet may
not require such profound T cell proliferation.
These murine models have advanced a number of
experimental concepts that are now being applied in the
clinic in an effort to reduce the incidence and severity of
GVHD while maintaining GVT, which could have a major
impact on results of allogeneic HCT because GVHD remains
the major obstacle to a successful outcome.
