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Peregrine
Pharmaceuticals, Inc.
today announced
data from studies validating the immune-stimulatory mechanism of
action of bavituximab and demonstrating that the combination of a
preclinical phosphatidylserine (PS)-targeting antibody with the
immune checkpoint inhibitors anti-CTLA-4 or anti-PD-1 antibodies
yielded superior anti-tumor immune responses in animal models of
melanoma and colon cancer compared to anti-CTLA-4 and PD-1 antibodies
alone. These data were presented yesterday and today as a
late-breaking poster presentation and a poster presentation,
respectively at the 105th Annual Meeting of the American Association
for Cancer Research (AACR) being held in San Diego, California from
April 5-9, 2014. Bavituximab is an investigational immunotherapy
currently being evaluated in second-line, non-small cell lung cancer
(NSCLC) as part of the SUNRISE pivotal Phase III clinical trial.
"Data from these combination studies are compelling as they provide
further evidence that support the immune-stimulatory effects of
bavituximab in reducing the prevalence of key immunosuppressive
checkpoints in the tumor environment, reducing tumor-suppressive
factors, reducing immune suppressor cells and providing increased
tumor-specific immunity," said Jeff T. Hutchins, Ph.D., vice
president of preclinical research at Peregrine. "These data also show
that when combined with downstream immune checkpoint inhibitors such
as anti-CTLA-4 and anti-PD-1, PS targeting mediates an improved
protective tumor-specific immunity following tumor rechallenge. While
these new downstream checkpoint inhibitors have been shown to
strengthen the tumor-killing activity of T-cells and thus extend
survival in some patients, there remains a need to increase the
number of responders that mount anti-tumor T-cell responses in order
to maximize the effects of these downstream checkpoint inhibitors. We
believe a PS-targeting antibody, such as bavituximab, plays a key
role in reducing tumor suppression and driving a more inclusive
immune-mediated response. Insights from these data will influence our
future clinical development plans including the soon to be opened
investigator-sponsored trial assessing the potential of bavituximab
and an anti-CTLA-4 antibody in patients with advanced melanoma."
In a poster titled: "Targeting of Phosphatidylserine by Monoclonal
Antibodies Enhances Activity of Immune Checkpoint Inhibitors in
Tumors," scientists from Peregrine Pharmaceuticals, led by Bruce
Freimark, Ph.D., director of pre-clinical research oncology, reported
that animals treated with the PS-targeting antibody ch1N11, the
preclinical equivalent to bavituximab, in combination with
anti-CTLA-4 or anti-PD-1 in melanoma and colon cancer tumor models
demonstrated greater delayed tumor growth and suppression than
anti-CTLA-4 or anti-PD-1 alone. Results also showed that the
combination with anti-CTLA-4 reduced M2 macrophages in the melanoma
tumor model, an important cell type responsible for facilitating
tumor growth and proliferation. In addition, in the preclinical
melanoma model, the combination of ch1N11 with anti-CTLA-4 or
anti-PD-1 antibody developed protective tumor-specific immunity to
tumor re-challenge than either the anti-CTLA-4 or anti-PD-1 antibody
alone. Lastly, results showed that the combination treatment of
ch1N11 and anti-PD-1 led to a proportional increase in tumor
infiltrating cytotoxic T-cells, while decreasing PD-L1 expression on
tumor derived CD45 cells such as tumor, endothelial and stromal cells
as compared to anti-PD-1 alone.
"We now have compelling evidence from these preclinical studies in
multiple tumor models that PS-targeting antibodies mediate a
fundamental immune-stimulatory shift in the tumor environment,
facilitating increased antigen presenting cells as well as
tumor-specific cytotoxic T-cells," said Peregrine's Dr. Freimark.
"With the use of immunohistochemical staining, we have seen that
tumors from animals treated with ch1N11 in combination with anti-PD-1
antibody showed faster and more complete T-cell and macrophage tumor
infiltration rates, which correlate with decreased tumor cells, than
anti-PD-1 alone. We look forward to further exploring the potential
of the bavituximab with other immune checkpoint inhibitors."
In a poster titled: "Phosphatidylserine-Targeting Antibody Synergizes
with anti-PD-1 Antibody to Inhibit Tumor Growth in K1735 Mouse
Melanoma Model," researchers from the University of Texas
Southwestern Medical Center summarized their findings that
PS-targeting antibodies block PS-mediated tumor immunosuppression
while reactivating tumor immunity at multiple levels. Specifically,
results showed that a PS-targeting antibody repolarized
tumor-associated macrophages (TAM) from an M2 to a M1-phenotype,
decreased the presence of myeloid-derived suppressor cells (MDSC),
promoted dendritic cell maturation into cells having the phenotype of
functional antigen presenting cells and elicited antitumor T cell
immunity. In addition, statistically signifcant differences were seen
in T-cell mediating markers IL-2 and gamma-interferon with the
ch-1N11 and PD-1 combination. Researchers concluded that the
combination of bavituximab with the anti-PD-1 checkpoint blockade
should synergistically induce potent long-lasting antitumor immunity.
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