The endothelium in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 481

rationale for studying inhibitors of neovascularization to enhance the anti-
tumor efficacy of allo-HSCT.

Inhibition of neovascularization to increase anti-tumor
immune responses and graft-versus-leukemia activity

We hypothesized that the inhibition of neovascularization increases graft-
versus-leukemia (GVL) activity after allo-HSCT. To test this hypothesis we
used murine allo-HSCT tumor models that included AML and B-lymphoma
[46] . In HSCT models without GVL activity (without donor T cells) we found
that the inhibition of neovascularization led to a moderate decrease in leu-
kemia/lymphoma growth without impact on survival. In a next step we
tested the combination of GVL activity (HSCT models with donor T cells)
and pharmacological inhibition of neovascularization with a monoclonal
antibody against VE-cadherin (E4G10). We found a synergy between GVL
activity and the inhibition of neovascularization leading to considerably
decreased tumor growth and a survival benefit of tumor-bearing HSCT
recipients [46] . The mechanism behind the synergy of antineovasculariza-
tion and GVL activity has not been discovered yet and has to be studied in
more detail. However, as discussed below, several possibilities exist as to
how antiangiogenic therapies may improve immunotherapy.

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An important mechanism of how inhibitors of neovascularization may
enhance the GVL activity is the temporary normalization of tumor vascula-
ture leading to improved tumor blood flow and consequently more effective
recruitment of donor T cells to the tumor tissue [78-80] . Although anti-
VEGF therapy eventually reduces the number of vessels in solid tumors,
VEGF/VEGFR blockade was found to initially stabilize and normalize ves-
sels, leading to transiently improved intratumoral blood flow. After a single
administration of anti-VEGF antibodies the normalization of tumor blood
vessels began within 6 h and lasted less than 5 days [81] . During this time
frame anti-VEGF treatment led to improved vessel functionality within
solid tumors characterized by improved tumor perfusion and reduced
tumor hypoxia [82] . These findings in preclinical models were confirmed
in a clinical study by Willett, Jain, and colleagues [80] . They found early
normalization of tumor vessels in patients with rectal carcinoma receiv-
ing preoperative administration of the anti-VEGF-A antibody bevacizumab
[80] . Given that anti-tumor immunotherapy depends on the tumor blood
flow, as well as on tumor oxygenation, it is reasonable to hypothesize that
a combination of inhibitors of neovascularization with anti-tumor immu-
notherapeutic strategies could be beneficial. This may also apply to the
powerful GVL effect in patients with malignancies after allo-HSCT. In sup-
port of this hypothesis several studies found more tumor-infiltrating T cells
when immunotherapy was combined with inhibitors of neovascularization
compared with immunotherapy alone [83-85] . Shrimali and Rosenberg [85]
investigated whether anti-VEGF strategies could enhance the effectiveness
of adoptive cell transfer in murine cancer models. The administration of
anti-VEGF antibodies led to increased infiltration of transferred cells into
the solid tumor, inhibition of tumor growth, and improved survival [85] .

Another mechanism of how inhibitors of neovascularization may augment
GVL effects is the enhancement of leukocyte infiltration in tumors after