Avid Bioservices Inc (CDMO)

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Peregrine Exhibiting & 3-Presentations Sept6-9 at IASLC World Conf. in Denver – recall, PPHM KOL/SAB’r Dr. David Carbone becomes President of The IASLC on 9-9-15. 3 Bavi presentations (1 poster, 1 Mini-Oral, 1 Oral) by UTSW (David Gerber, Rolf Brekken, Xianming Huang) and Moffitt CC (Scott Antonia), all with Peregrine co-authors…

Sept6-9 2015: “IASLC’s 16th World Conf. on Lung Cancer”, Denver
http://wclc2015.iaslc.org/
“The World Conference on Lung Cancer (WCLC) is the world’s largest meeting dedicated to lung cancer and other thoracic malignancies. More than 7,000 delegates come from more than 100 countries to discuss the latest developments in thoracic malignancy research. Attendees include surgeons, medical oncologists, radiation oncologists, pulmonologists, radiologists, pathologists, epidemiologists, basic research scientists, nurses, allied health professionals, advocates, and patients.”
http://www.iaslc.org/events/16th-world-conference-lung-cancer
2015 Exhibitor: Peregrine Pharm. (1 of 39) - booth #1724 (adjacent to Abbvie)
• RECALL: PPHM KOL/SAB Dr. David Carbone becomes President of IASLC 9-9-15 ( https://www.iaslc.org/about-us/board ). “…I also personally find it rewarding to participate in the global fight against cancer, and am honored to have been elected President of the IASLC, eff. Sept. 9, 2015." http://www.supportohiostate.org/site/TR?px=1009121&fr_id=1151&pg=personal
• IASLC Faculty & Staff Disclosures: Heather A. Wakelee, MD - Grant/Research Support: Genentech/Roche, Lilly, Pfizer, Novartis, Exelixis, Xcovery, AstraZeneca, Clovis, Regeneron; Consultant: Peregrine. http://www.gotoper.com/conferences/ilc/meetings/15th-international-lung-cancer-congress “Associate Prof. of Medicine, Div. of Oncology; Faculty Director, Cancer Clinical Trials Office; Co-leader, Lung Cancer Disease Mgt Group, Stanford Univ. School of Medicine, Stanford CA”
PGM-Search: http://content.webges.com/library/wclc/browse/search

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WCLC 2015 Track: Treatment of Advanced Diseases - NSCLC
9/7/15 9:30am-5:00pm, Exhibit Hall (Hall B+C)
POSTER #P1.01-075: “Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)
David R. Spigel, Joseph Shan, Alberto Chiappori, Ulrich Keilholz, Martin Reck, Martin Edelman, Manuel Domine, Keunchil Park, Tae Won Jang, Wu-Chou Su, Rachel E. Sanborn, Leora Horn, Rebecca Heist, Paul Mainwaring, David E. Gerber (UTSW)
ABSTRACT…
BACKGROUND: Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-B and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-a and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous NSCLC, bavituximab 3 mg/kg + docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 mos) in median overall survival (OS) compared to control.
METHODS: SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in Dec.2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and 2 interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every 2 cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.
RESULTS: Trial in progress
CONCLUSION: Trial in progress

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WCLC 2015 Track: MINI ORAL #14 - Pre-Clinical Therapy (ID 119)
Moderators: Lynnette Fernandez-Cuesta Adi F. Gazdar
9/8/15, 10:45am-12:15pm, Mile High Ballroom 2c-3c
MINI-ORAL #14.07: “Bavituximab Activates CD8+ TILs in a 3D Ex Vivo System of Lung Cancer Patients Derived Tumors With Negative PD-L1 Expression”
Soner Altiok, Melanie Mediavilla Valera, Jenny Kreahling, Nikoletta L. Kallinteris, David Noyes, Tiffany N. Razabdouski, Joseph Shan, Jeff Hutchins, Kerstin Menander, Scott J. Antonia (Moffitt CC)
ABSTRACT…
BACKGROUND: Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Bavituximab blocks PS-mediated immune suppression and activates cytotoxic T lymphocyte anti-tumor responses.
METHODS: Tissues from consented patients with adenocarcinoma of the lung were extracted at the time of surgical resection and disaggregated to characterize expression of immune checkpoint proteins such as PD-1, CTLA-4, LAG3, TIM3, BTLA and adenosine A2A receptor on both CD4+ and CD8+ tumor infiltrating cells by flow cytometry (FACS) and stained for PD-L1, CD68, and CD163 via immunohistochemistry (IHC). 3D tumor microspheres were prepared and treated ex vivo with an IgG control, F(ab)’2 version of bavituximab, bavituximab, docetaxel, anti-PD-1 or PD-L1 and combinations of bavituximab, anti-PD-1 or PD-L1 and docetaxel for 36 hours within an intact tumor microenvironment. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by treatment. In a few cases, the expanded TILs were tested in PDX models using the consented patient’s tumor.
RESULTS: Bavituximab induces activation of TILs in 3D ex vivo tumor microsphere models of lung cancer, as demonstrated by a significant increase in IFN-y, TNF-a, and GM-CSF secretion. FACS, IHC, and NanoString gene function analysis read out assays revealed that this effect was associated with low PD-1 expression on CD8+ cells, negative PD-L1 expression in the stating biopsy tissue, and a conversion of the M2 to M1 macrophage phenotype.
CONCLUSION: These data support the use of bavituximab as an immunomodulatory treatment in adenocarcinoma of the lung by enhancing the activation of CD8+ TIL derived from patients' tumors with negative PD-L1 expression; correlating with increased cytokine production by lymphoid cells and repolarization of myeloid cells from an immunosuppressive to an immune active state.

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WCLC 2015 Track: ORAL #41 - Immune Biology, Microenvironment & Novel Targets (ID 159)
Moderators: Sukhmani K. Padda, Raphael Nemenoff
9/9/15, 6:30-8:00pm, Four Seasons Ballroom F1+F2
ORAL #41.05: “Targeting Phosphatidylserine-Mediated Immune Suppression Enhances the Efficacy of Immune Checkpoint Blockade in Pre-Clinical Tumor Models”
Rolf A. Brekken (UTSW), Bruce Freimark, Jian Gong, Carrie Baldwin, Van Nguyen, Michael Gray, Shen Yin, Jeff Hutchins, Alan Schroit, Xianming Huang (UTSW)
ABSTRACT…
BACKGROUND: Despite substantial progress, only a subset of cancer patients benefit from blockade of the PD-1 immune checkpoint. Multifocal immune suppression in the tumor microenvironment is the underlying cause for the limited efficacy of immune checkpoint blockade. Persistent immune suppression prevents the development of a robust T cell response to tumor specific antigens that is required for effective downstream immune checkpoint blockade. An underappreciated but significant contributor to immune suppression in tumors is the expression of the membrane phospholipid phosphatidylserine (PS) on the surface of tumor cells and tumor-derived microvesicles. PS is recognized by receptors on immune cells where it triggers the secretion of immune suppressive cytokines, prevents the differentiation of myeloid-derived suppressor cells (MDSCs) and inhibits dendritic cell (DC) maturation; events that prevent a productive anti-tumor T cell response. Bavituximab, a chimeric monoclonal antibody that targets PS and inhibits PS-mediated immunosuppressive signaling, drives immune activation by reducing the levels of MDSCs, by polarizing tumor-associated macrophages towards an M1 phenotype and by promoting the maturation of dendritic cells (DCs).
METHODS: The efficacy of bavituximab, anti-PD-1 and combination therapy was evaluated in multiple syngeneic, pre-clinical tumor models. Treatment efficacy was determined by inhibition of tumor growth and by immunophenotyping of spleen and tumor infiltrating leukocytes.
RESULTS: The combination of antibody-mediated PS and PD-1 blockade was significantly more effective in reducing tumor burden and promoting immune activation than single agent therapy. Combination therapy increased tumor infiltration of effector T-cells (Teff), increased the Teff:T regulatory cell ratio in the tumor and enhanced Teff function as determined by IFN-y, TNFa and granzyme B levels associated with Teff cells in the spleen and tumor. Furthermore combined blockade of PS and PD-1 signaling reduced the level of immune suppressive cells (e.g., MDSCs, M2 macrophages, and Treg) in the tumor microenvironment.
CONCLUSION: These results raise the possibility that PS blockade with bavituximab can enhance the efficacy of anti-PD-1 therapy even in patients with tumors that are unresponsive to single agent immune checkpoint therapy.