The endothelium in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 480

authors found that a neutralizing anti-VEGFR2 monoclonal antibody
inhibited leukemic cell survival in vitro and blocked VEGF-mediated pro-
liferation of leukemic cells, demonstrating the biologic relevance of VEGF
for leukemia growth. Similar results were found when the proangiogenic
factor angiopoietin was studied: primary human AML cells express angio-
poietin, and blocking angiopoietin interactions with the Tie2 receptor leads
to decreased proliferation of AML blasts [66] . In patients with AML a high
angiopoietin 2 expression on leukemic blasts is positively correlated with
inferior outcome, suggesting that angiogenesis stimulation is a clinically
significant process during the growth of hematologic malignancies [67] .
These interesting results prompted in vivo studies on anti-VEGF therapies
to treat leukemia. In preclinical models it has been demonstrated by several
groups that VEGF blockade results in decreased leukemia growth [68-72] .
In a clinical phase II study 48 patients with refractory or relapsed AML were
treated with a combination of chemotherapy and bevacizumab leading to
48% overall response and 33% complete response, respectively. The authors
concluded that bevacizumab yields a favorable complete response rate in
adults with AML that is resistant to traditional treatment approaches [73] .
Taken together these data suggest that the inhibition of neovascularization
could be a novel therapeutic target in hematologic malignancies.

486

Inhibition of neovascularization as a mechanism of
allogeneic immune responses against malignancies

Since 2000 important knowledge has been gained regarding the inhibition
of neovascularization as a mechanism of action of T-cell therapies against
cancer. There is an increasing body of evidence showing that T cells not only
directly interact with tumor cells, but also target tumor vasculature during
allogeneic immune responses against malignancies.

In animal models using syngeneic and allogeneic solid tumors (hepatoma)
it was demonstrated that tumor rejection depends on stromal events affect-
ing the tumor environment [74] . Damage to the tumor neovasculature,
mediated by host leukocytes, was a prerequisite to tumor rejection. Qin
and Blankenstein [75] showed that CD4 + immunity against MHC II tumors
depends on the inhibition of tumor angiogenesis as a result of interferon-γ
(IFN-γ) release [75] . They used various primary solid tumors from IFN-γ-R +/−
as well as from IFN-γ-R −/− mice. In the absence of IFN-γ tumor blood ves-
sels were observed at early time points. In contrast, blood vessels within the
tumor were completely absent and the tumor became necrotic in the pres-
ence of IFN-γ. The authors concluded that CD4 + T-cell-dependent tumor
immunity involves tumor destruction indirectly by inhibition of angiogen-
esis. In line with these results it was demonstrated in a preclinical pancre-
atic carcinoma model that T-antigen-specific CD4 + T cells home selectively
into the tumor microenvironment and inhibit tumor neovascularization
through release of antiangiogenic chemokines [76] . In the HLA-matched
setting, which is of specific interest to allo-HSCT, it was demonstrated that
transferred CD8 + T cells primed against a minor antigen led to solid tumor
rejection through inhibition of tumor neovascularization [77] .

These scientific findings demonstrate that inhibition of neovasculariza-
tion contributes to anti-tumor effects of allogeneic T cells and provide the