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Re: cjgaddy post# 147996

Friday, 12/20/2013 2:04:45 PM

Friday, December 20, 2013 2:04:45 PM

Post# of 345554
New Dec’13 PAN-EU article on Bavi/PS by Dr.Brekken (PPHM SAB) & Xianming Huang (former Phil Thorpe Lab; now Rolf Brekken Lab) which reviews bavituximab’s ability to reverse PS-mediated immunosuppression and initiate an effective adaptive antitumor activity…
“Our results indicate that antibody-mediated PS blockade with bavituximab reverses PS-mediated immunosuppression and initiates therapeutically effective adaptive anti-tumor immunity. Thus, treatment with bavituximab in combination with a blockade of downstream immune checkpoints could result in robust and long-lasting anti-tumor immunity that significantly improves clinical outcomes.”

Pan European Network’s Science & Technology Journal
Dec.2013 Issue: http://www.paneuropeannetworks.com/ST9/
…Pg163: http://www.paneuropeannetworks.com/ST9/#162
“Revitalizing Tumor Immunity - Immunosuppressive signals from PS help tumors evade immune surveillance as detailed by investigators at UT Southwestern”
By: Xianming Huang & Rolf A Brekken - Hamon Center for Therapeutic Oncology Research, UTSW-MC/Dallas [ http://www.utsouthwestern.edu/labs/brekken ]

COVER:


Article (Dec.2013):




TEXT: Dec.2013, Pan European Network’s Science & Technology Journal
“Revitalizing Tumor Immunity” – R.Brekken/X.Huang – UTSW/Dallas
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Phospholipids are distributed asymmetrically in the plasma membrane of most normal eukaryotic cells. Unlike neutral phospholipids that are randomly distributed across the bilayer membrane, phosphatidylserine (PS) is predominantly localized in the inner membrane leaflet. The asymmetric distribution of PS is actively maintained by an ATP-dependent aminophospholipid translocase.

During apoptosis, PS is externalised to the outer plasma membrane leaflet where it functions as an ‘eat me’ signal that facilitates the recognition and clearance of dying cells. PS-dependent engulfment of apoptotic cells triggers a series of events that leads to the generation of potent immunosuppressive signals that quells any potential autoimmune responses. Thus, PS exposure represents an evolutionarily conserved mechanism of immune suppression.

Tumors have hijacked this biology such that exposure of PS in the tumor microenvironment is critical in maintaining the immunosuppressive state of tumors. Externalized PS is abundant in the tumor microenvironment: it is found on tumor vascular endothelial cells, on tumor-derived micro vesicles, and constitutively on some tumor cells. Moreover, the exposure of PS is increased significantly on tumor cells undergoing apoptosis in response to chemotherapy and radiotherapy. Externalized PS interacts with PS receptors on immune cells where it actively promotes expansion of immunosuppressive cells that enhance tumor progression and prevent induction of adaptive tumor immunity. Based on these observations we propose that PS exposure is an upstream immune checkpoint that is exploited by successful tumors.

PS blockade
To explore the possibility of reversing the immunosuppressive effects of exposed PS, we raised a family of PS-targeting antibodies that bind PS with high affinity. For example, bavituximab, a chimeric PS targeting antibody is currently in multiple Phase II clinical trials. Data obtained in several preclinical tumor models indicate that antibody mediated PS blockade reactivates tumor immunity on multiple levels. It re-polarises tumor associated macrophages from an immunosuppressive to a tumoricidal phenotype, it decreases the presence of immunosuppressive myeloid derived suppressor cells (MDSCs) and promotes their differentiation, it promotes dendritic cell maturation into functional antigen presenting cells, and induces tumor specific cytotoxic T-cell immunity. Thus, antibody mediated PS blockade promotes innate and adaptive tumor immunity.

Impressive anti-tumor effects have been obtained in cancer patients by a blockade of immune checkpoints (e.g. antibodies specific for PD1, PD1L, and CTLA4). However, only a limited number of patients benefit these therapies. Mechanistic studies indicate that blockade of these immune checkpoints are most effective when there is a de novo or pre-existing anti-tumor immune response. Unfortunately, pre-existing tumor specific immune activity is limited in cancer patients because of the exposure of PS in the tumor microenvironment.

Our results indicate that antibody-mediated PS blockade with bavituximab reverses PS-mediated immunosuppression and initiates therapeutically effective adaptive anti-tumor immunity. Thus, treatment with bavituximab in combination with a blockade of downstream immune checkpoints could result in robust and long-lasting anti-tumor immunity that significantly improves clinical outcomes.
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For more information please see Yinet al 2013 Cancer Immunology Research doi:10.1158/2326-6066. [ 8-19-13: http://tinyurl.com/mhjftka ] *end article*

About: PAN EUROPEAN NETWORKS: SCIENCE & TECHNOLOGY
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http://www.paneuropeannetworks.com/science-publications/science-technology-publication/

= = = = = = = = = = = =FYI:
No surprise, but Science Magazine has selected Cancer Immunotherapy as its Breakthrough of the Year (Dec.2013 issue).
=> http://news.sciencemag.org/breakthrough-of-the-year-2013


ALSO, this most compelling quote from a new NATURE article (pub. 12-19-13), ”Bacteriology: A Caring Culture”, a special article on Dr. William Coley's** legacy and modern efforts to defeat cancer [ http://www.nature.com/nature/journal/v504/n7480_supp/full/504S4a.html?WT.ec_id=NATURE-20131219]
" Hal Gunn (CEO, Qu Biologics) and his colleagues speculate that their SSIs reset the immune system by mimicking the beneficial effects of infection at a tumor site. In particular, they believe that SSI molecules alter the activity of macrophages, a type of cell involved in the early stages of an immune response. The SSIs, they say, cause macrophages to shift from a response involved in tissue repair and cancer growth to a response that promotes the destruction of abnormal cells."
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As my PHD Friend recently told me about the above quote => “Just what Bavi does!”
**Dr. William B. Coley, a surgeon who made the first attempts at the non-surgical treatment of cancer through stimulation of the immune system. For this reason, Dr. Coley has become known as the "Father of Cancer Immunotherapy."
http://en.wikipedia.org/wiki/William_Coley

By Djohn iHub #152767 12-20-13: I found this helpful in understanding the 12-2013 Brennan/Huang Pan-EU article…
8-27-10: “Macrophages: The 'Defense' Cells That Help Throughout the Body”
http://www.sciencedaily.com/releases/2010/08/100826141232.htm

= = = = = =
BAVI MOA 11-9-13: Annual SITC (WashDC) – 2 posters about Bavi’s Immunostimulatory MOA http://tinyurl.com/mjaweu5
...“We are actively working towards initiating a clinical trial in the coming months to further investigate the potential synergistic effects of bavituximab and an approved [anti-CTLA-4] immunotherapy in patients with Melanoma."
O. 6th IST Trial: Bavi+Ipilimumab(Yervoy) vs. Adv.Melanoma (Ph1b, random, open-label, 2arms, n=24)
Protocol (UTSW): http://www.clinicaltrials.gov/ct2/show/NCT01984255 (Est Start: Jan.2014)
…Note: Ipilimumab = BMS’s “Yervoy” (anti-CTLA-4) http://www.yervoy.com

10-28-13 IASLC/Sydney: “Immune Checkpoints in the Tumor Environment: Novel Targets & the Clinical Promise of Combined Immunotherapies” http://tinyurl.com/mjaweu5
…Symposium speakers: Scott J. Antonia/MD-PhD(H.Lee Moffitt CC), Dmitry I. Gabrilovich/MD-PhD(Wistar Inst), Rolf A. Brekken/PhD(UTSW), David E. Gerber/MD(UTSW)

BAVI MOA: 8-19-13 Data Supporting Bavituximab’s Immunotherapy MOA Published in “Cancer Immunology Research” (AACR) - http://tinyurl.com/mhjftka (PDF)
…“PS-Targeting Antibody Induces M1 Macrophage Polarization & Promotes Myeloid-Derived Suppressor Cell Differentiation” (Thorpe etal)

BAVI MOA: 8-13-13 PPHM/VP Dr. Jeff Hutchins’ Presentation on the Downstream Immunostimulatory Effects/Moa of PS-targeting antibodies (like Bavi) at CHI’s “Immunotherapies Congress”/Boston http://tinyurl.com/m6h2tvt
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