Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

15.3
Graft-versus-Tumor (GvT)Effect
Barnes in 1956 first suggested the existence of a GvT effect in experimental models,
which Math termed ªadoptive immunotherapyº in 1965 [7]. Landmark articles describing
graft-versus-leukemia (GvL) effects in human marrow allograft recipients
were published by Weiden in 1979 and 1981 [8]. In these studies, the Seattle group
reported that leukemia relapse rates following allogeneic BMT were markedly less in
patients who developed GvHD as compared with those who did not. Horowitz studies
on relapse rates following allogeneic and syngeneic BMT, showed that relapse
rates are lower in patients who develop both acute and chronic GvHD, higher in
those who develop no clinically evident GvHD, and higher still if T cells are depleted
from the marrow graft or in recipients of twin transplants [9]. These observations led
to the hypothesis that the GvT response is mediated by immunologically competent
donor cells and that these cells could be used therapeutically to induce a direct GvT
reaction. The strongest evidence of GvT came from the observation that many patients
who relapse after allogeneic BMT can be reinduced into long-term remission
by simply infusing additional donor lymphocytes [10]. Table 15.4 summarizes the
evidence supporting an allogeneic GvL effect.
15.4
Donor Lymphocyte Infusions (DLIs)
Since the first report of Kolb in 1990, DLIs have been widely used as treatment of
disease recurrence after allogeneic BMT [11±14]. From these large series of DLIs,
major differences emerged among malignancies in their susceptibility to GvL effects.
Table 15.5 shows results from the European Blood and Marrow Transplantation
Group (EBMT) DLI study. Chronic myelogenous leukemia (CML) is the most sensitive
leukemia, with a probability of complete cytogenetic remission after DLI of 80 %
with an overall survival at 5 years of 80%, in patients with cytogenetic relapse; in the
case of disease recurring in transformed phase, the response rate to DLI and 5-year
probability of survival are 36 and 25%, respectively. In the study reported by Collins
et al. [13], the response rate and actuarial probability of long-term complete remissions
(CRs) are comparable to the EBMT study. Remissions have been reported in
patients who relapse soon after undergoing transplantation because of discontinuation
of immunosuppressive therapy without DLI; the discontinuation of immuno-
Tab. 15.4 Evidence supporting an allogeneic GvLeffect
15.4 Donor Lymphocyte Infusions (DLIs)
Demonstration of minimal residual disease present early after high-dose therapy
Reduced risk of relapse in patients with acute and chronic GvHD
Increased risk of relapse after syngeneic and T cell-depleted transplants
Induction of remission by DLIs in patients relapsing post-BMT
Demonstration of reactivity of donor-derived T cell clones against malignant cells
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