Peregrine Pharmaceuticals,
Inc. PPHM PPHMP, a biopharmaceutical company focused on
developing therapeutics to stimulate the body's immune system to fight
cancer, today announced results from multiple new preclinical studies
demonstrating enhanced anti-tumor activity and immune activation for
combinations of a preclinical bavituximab equivalent and checkpoint
inhibitors such as anti-PD-1 and anti-CTLA-4 in preclinical models of breast
cancer and melanoma. Additionally, the company announced preliminary
results for a new clinical test specifically designed to illustrate how
bavituximab, the company's investigational phosphatidylserine (PS)-signaling
pathway inhibitor, modulates immune responses in the tumor microenvironment.
Results from these studies were presented at the 2015 annual meeting of the
Society for Immunotherapy of Cancer (SITC), which was held in National
Harbor, MD, on November 4 - 8, 2015.
"The positive data presented at SITC with regard to combinations of
bavituximab and checkpoint inhibitors further support our belief that
bavituximab has the potential to be a critical component of innovative
combination cancer immunotherapies," said Jeff T. Hutchins, vice president
preclinical development of Peregrine. "Particularly exciting is the new
data in animal models of breast cancer which showed that a significantly
greater number of subjects demonstrated anti-tumor activity when treated
with the combination of bavituximab and anti-PD-1 as compared to treatment
with anti-PD-1 alone. Additionally, combination treatment led to prolonged
protection for animals as evidenced by their lack of new tumor development
when later re-challenged with the same tumors."
Bavituximab is an investigational immunotherapy designed to assist the
body's immune system by targeting and modulating the activity of
phosphatidylserine (PS), a highly immune-suppressive signaling molecule
expressed broadly on the surface of cells in the tumor microenvironment.
Peregrine's PS signaling pathway inhibitor candidates, including
bavituximab, reverse the immunosuppressive environment that many tumors
establish in order to proliferate, while also fighting cancer by activating
immune cells that target and fight cancer. The preclinical equivalent of
bavituximab, ch1N11, is used in animal model studies as a guide for clinical
development.
Breast Cancer
Researchers from Duke University and Peregrine evaluated the combination of
ch1N11 (preclinical bavituximab equivalent) and anti-PD-1 therapy versus
anti-PD-1 stand-alone therapy in well-characterized murine breast cancers,
including the triple negative breast cancer (TNBC) model E0771. Study data
showed that the combination therapy significantly enhanced overall survival
(p=0.0016) and was capable of mediating complete tumor regressions in a
greater number of subjects compared to single agent treatments (60% vs.
20%). Data also demonstrated that animals receiving combination treatment
had significant increases in tumor associated indicators of immune system
activation, including CD45+, CD8+ and CD3+ T-cells. Importantly, the
combination treatment led to a prolonged anti-tumor immune response which
protected the animals against a re-challenge with the same tumor. This
sustained anti-tumor response suggests the potential of the combination
therapy to trigger immune system memory and support adaptive immune
responses against reemerging disease in breast cancers. All study animals
experienced no signs of adverse effects following repeated doses of all
therapeutic agents.
Melanoma
In follow-on work, researchers from the University of Texas, Southwestern
and Peregrine evaluated combinations of ch1N11 and checkpoint inhibitors
(anti-PD-1 or anti-CTLA-4) versus each agent as a stand-alone therapy in
common models of melanoma (B16F10 and K1735). Data showed that the
combinations of ch1N11 with either anti-PD-1 or anti-CTLA-4 led to
significantly greater levels of tumor infiltrating CD8+ T cells than any of
the three agents alone. Additionally, findings demonstrated that the
combination therapies were more effective at shifting the tumor
microenvironment from immunosuppressive to immune active than the single
agents, as shown by greater increases in the ratio of T effector cells to T
regulatory cells, reactivation of tumor infiltrating T cells and restoration
of the effector function of the tumor infiltrating T cells. This activity
was more pronounced for the ch1N11/anti-PD-1 combination than for the
ch1N11/anti-CTLA-4 combination. Based on these data, study investigators
concluded that ch1N11 synergizes with checkpoint inhibitors to induce strong
tumor specific CD8 T cell immunity.
"There is an extensive and growing collection of data that demonstrates that
phosphatidylserine directly triggers broad immunosuppression in the tumor
microenvironment and contributes to resistance to checkpoint inhibitor
therapy. By targeting and blocking PS, bavituximab appears able to shift
the tumor environment from immunosuppressive to immune active and, in turn,
enhance the anti-tumor activity of checkpoint inhibitors such as anti-PD-1
and anti-CTLA4," said Bruce Freimark, Ph.D., director of pre-clinical
oncology of Peregrine. "This latest data in well validated models of
multiple tumor types further support our belief that bavituximab may be able
to play an essential role in combination immuno-oncology treatment regimens.
With this in mind, we are committed to evaluating the agent's potential in
combination with a range of cancer therapies against various cancer types."
ImmunoProfiling
Researchers presented preliminary results for a new custom assay designed to
provide detailed profiles of immune activity in patient tumors. The
Opal(TM) 6-plex quantitative immunofluorescence (IF) assay is specifically
designed to measure the level and type of lymphocytes, myeloid and dendritic
cell subsets found within the tumor microenvironment. This information is
important as it can be used to correlate immune response parameters with
bavituximab treatment outcome and patient survival.
Presented results demonstrated that the Opal assay could reliably detect,
measure and phenotype lymphocytes and monocytes present in tumor tissues
from rectal adenocarcinoma, hepatocellular carcinoma and advanced melanoma
patients treated with bavituximab combination therapies. Importantly, the
findings were able to show changes in key indicators of immune activation,
including CD8+, CD4+ and regulatory T-cells, as well as myeloid and
dendritic cells, in the tumor microenvironment following bavituximab
treatment. The ability of this new assay to accurately measure specific
immune responses is expected to provide important additional information to
assist in Peregrine's ongoing development efforts for bavituximab. This
will be particularly valuable as the company works to better elucidate the
connection between the drug candidate's impact on immunomodulation and
patient response to treatment.
"We are very pleased with the performance of the Opal assay, particularly
its ability to compare the interaction of up to six phenotypic and
functional markers on a single slide of tissue. The power and prognostic
value of such immune activity assessments in the area of cancer was
initially established by the Immunoscore(R), and we believe the Opal assay
represents an important evolution of that work," said Bernard A. Fox, Ph.D.,
Harder Family Endowed Chair for Cancer Research, Member and Chief, Molecular
and Tumor Immunology, Earle A. Chiles Research Institute, Providence Cancer
Center; a world-renowned translational cancer immunotherapist; a founding
member of the Immunoscore steering committee. "I am looking forward to
continued collaboration with Peregrine to further optimize and validate this
assay to improve our understanding of immune infiltrate in tumors thereby
facilitating the rational design and use of bavituximab in combination with
novel and standard therapies."
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