Saturday, November 09, 2013 9:56:15 AM
11-9-13/SITC(WashDC) & 10-28-13/IASLC(Sydney) – large post in 2 sections:
A. 11-9-13: 2 Peregrine Posters at SITC/Wash - both on the blockage of PS-mediated immunosuppressive checkpoints by PS-Targeting antibodies. “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."
B. 10-28-13 IASLC/Sydney - PPHM sponsored symposium, “Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies” (Sydney, AUS) – see MLV’s Dr. George Zavoico’s 11-8-13 Sydney recap at the end.
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A. 11-9-13: 2 Peregrine Posters at SITC/Wash - both on the blockage of PS-mediated immunosuppressive checkpoints by PS-Targeting antibodies (incl. Bavituximab) – Abstracts & Images of Poster PDF’s below…
SITC = Society for Immunotherapy of Cancer
Nov7-10 2013 “28th Annual Meeting of the Society for Immunotherapy of Cancer (SITC)”, WashDC
“The yearly SITC Annual Meeting & Associated Programs serve as the primary SITC organized events and the premier destination for scientific exchange, education, and networking in the cancer immunotherapy community… By bringing together over 800 domestic & intl. basic, clinical, and translational scientists from academia, gov’t, and the biotech/pharmaceutical industry, in an interactive, educational environment, SITC's scientific programming helps bridge the "bench to bedside" gap between translational research, development, and clinical practice.”
http://www.sitcancer.org/2013
Schd: SITC: http://www.sitcancer.org/2013/annual-meeting/schedule
Abstracts: http://www.immunotherapyofcancer.org/supplements/1/S1/all
... Journal for ImmunoTherapy of Cancer 2013, (Suppl1 (7Nov2013)
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Peregrine’s 2 Posters:
Poster #172 (P151) “Targeting of Phosphatidylserine by Monoclonal Antibodies Reverses an Immunosuppressive Checkpoint Inducing Innate and Specific Anti-Tumor Responses”
Jian Gong, Rich Archer, Van Nguyen, Jeff Hutchins, Bruce Freimark (Peregrine)
ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed on tumor vascular endothelial cells (ECs) and tumor cells, and exposure is enhanced in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. PS exposure in tumors promotes an immunosuppressive microenvironment which includes the recruitment of myeloid derived suppressor cells (MDSCs) and M2-like macrophages as well as the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumors and their secreted microparticles triggers a Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses this immunosuppressive, PS meditated checkpoint thereby enhancing anti-tumor immunity. A chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using syngeneic tumors and human tumor xenografts in mice, we demonstrate PS targeting antibodies specifically localize to PS exposed on membranes of tumor blood vessels, tumors, tumor-infiltrating inflammatory cells and microparticles. Analysis of blood, spleens and tumor tissue demonstrates that PS targeting antibodies are capable of suppressing tumor growth in multiple tumor types by several mechanisms including destruction of tumor blood vessels by ADCC mechanisms, blockage of the PS-mediated immunosuppressive checkpoint, and reactivation of M1 macrophages, dendritic cell maturation and T-cell cellular anti-tumor responses. The combination of these mechanisms promotes strong localized anti-tumor responses without the side-effects of systemic immune activation.
http://www.immunotherapyofcancer.org/content/1/S1/P151
Poster #176 (P154) ”Phosphatidylserine-targeting Antibody Induces M1 Macrophage Polarization, Promotes Myeloid Derived Suppressor Cell Differentiation and Boosts Tumor-Specific Immunity”
Xianming Huang, Yi Yin, Dan Ye, Rolf Brekken, Philip Thorpe (UTSW)
ABSTRACT: Phosphatidylserine (PS) is a potent immunosuppressive lipid typically segregated to the inner leaflet of the plasma membrane. PS is externalized on tumor vasculature, tumor-derived exosomes, and tumor cells in the tumor microenvironment and externalization is markedly enhanced by therapy (e.g., radiation, chemotherapy, and/or androgen deprivation). Externalized PS interacts with immune cells where it actively promotes immunosuppression and tumor progression by expansion of myeloid derived suppressor cells (MDSCs) and M2-like tumor associated macrophages (TAMs). Bavituximab is a PS-targeting antibody that is being evaluated in multiple late-stage clinical trials in cancer patients. Here we show that treatment of PC3 tumor-bearing mice with 2aG4, a murine-version of bavituximab, significantly depleted M2-likeTAMs and MDSCs and increased the presence of M1-like TAMs and mature dendritic cells. In addition, PS blockade markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. Furthermore, in the immune-competent TRAMP mouse prostate tumor model, combination treatment of anti-PS antibody with castration induced strong tumor-specific T-cell immunity that resulted in significantly improved tumor free long-term survival and apparent cures in 35% of the animals, compared to no long-term survivors in groups treated with either single agent. In vitro studies confirmed that anti-PS re-polarized TAMs from an M2 to M1-like phenotype and drove MDSCs to differentiate into M1-like macrophages and functional dendritic cells. These data suggest that PS expression on the external cell surface defines an upstream immune checkpoint that is primarily responsible for expansion of MDSCs and M2-like TAMs in tumors. The results further support that blockade of the PS signal by bavituximab treatment can reverse this immune checkpoint suppression and promote therapeutically effective anti-tumor immunity.
http://www.immunotherapyofcancer.org/content/1/S1/P154
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11-8-13 Peregrine Press Release about SITC 2013:
Data Presentation at Society for Immunotherapy of Cancer (SITC) Annual Meeting Supports Potential of Peregrine Pharmaceuticals' Novel Immunotherapy Bavituximab in Combination with Anti-CTLA-4 Antibodies
• Phosphatidylserine (PS) and CTLA-4 Targeting Antibody Combination Stopped Tumor Growth in 100% of Animals in Preclinical Melanoma Model
• Planning Underway for Near-Term Phase I Clinical Trial Evaluating Bavituximab and Anti-CTLA-4 Combination Immunotherapy in Patients With Advanced Melanoma
TUSTIN, 11/08/13: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) today announced the presentation of data at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, Maryland being held November 7-10. The data showed that phosphatidylserine (PS)-targeting antibodies reactivate tumor immunity at multiple levels and that these antibodies, when combined with an anti-CTLA-4 antibody, an FDA-approved immunotherapy, yielded enhanced anti-tumor activity in a pre-clinical model of melanoma. Peregrine is planning to initiate a Phase III clinical trial in second-line non-small cell lung cancer with its lead PS-targeting antibody bavituximab by year-end.
In the presentation [#172/P151] titled: "Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses," scientists from Peregrine and The University of Texas Southwestern Medical Center examined the anti-tumor response of a PS-targeting antibody equivalent to bavituximab and anti-CTLA-4 combination therapy in a mouse melanoma model. Results showed that the group (n=12) that received the combination resulted in superior tumor growth inhibition than with either antibody alone with no additional toxicity following multiple treatment doses. In addition, histopathological analysis showed the combination produced more inflammatory cell infiltration and tumor destruction than anti-CTLA-4 alone.
"The results presented at SITC demonstrate that PS-targeting antibodies can block PS-mediated immunosuppression while simultaneously activating the immune system and that these effects can greatly improve the number of subjects responding to anti-CTLA-4 immunotherapy," said Jeff T. Hutchins, Ph.D., Vice President of Preclinical Research at Peregrine. "We believe the encouraging preclinical combination treatment data are due in part to the ability of bavituximab to facilitate an increase in tumor-specific cytotoxic T-cell activity, a function that appears to expand and broaden the potential of immunotherapeutic agents including anti-CTLA-4 and anti-PD-1 which prime and sustain T-cell mediated killing of tumor cells in our pre-clinical models. We are continuing to explore these and other immunotherapy combinations and look forward to reporting additional results as they become available."
In the presentation [#176/P154] titled: "Phosphatidylserine-targeting antibody induces M1 macrophage polarization, promotes myeloid derived suppressor cell differentiation, boosts tumor-specific immunity," researchers from The University of Texas Southwestern Medical Center showed that equivalents of bavituximab facilitated a tumor-localized decrease in immunosuppressive cytokines and immune cells, while inducing an increase in immunostimulatory cytokines, tumor-fighting M1 macrophages, mature dendritic cells and tumor-specific cytotoxic T-cells.
"These encouraging data further support the potential of giving bavituximab to enhance the potential of other immunotherapies such as anti-CTLA-4 antibodies. Our goal is to now advance this combination into clinical studies as part of our plans to obtain further proof of concept data for novel immunotherapy combinations including bavituximab," said Joseph Shan, MPH, vice president of clinical and regulatory affairs at Peregrine. "Recent clinical data have shown that immunotherapies can enhance tumor-specific T-cell responses resulting in promising survival benefits in some patients. We believe that bavituximab, by breaking immune tolerance in tumors and activating both the innate and adaptive immune system, holds the potential to allow more patients to respond to immunotherapies such as anti-CTLA-4 antibodies that target other checkpoints in the immune cascade. As such, 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 immunotherapy in patients with melanoma."
PRESENTATION DETAILS
Poster #172 “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses”
Jian Gong, Xianming Huang, Van Nguyen, Richard Archer, Jeff Hutchins, Steven King, Bruce Freimark, Peregrine Pharmaceuticals, Inc., Tustin, CA, Univ. of Texas SW Medical Center, Dallas, Texas
When: Saturday, Nov. 9th 6:15-7:15 PM
Location: Gaylord National Hotel & Convention Center, Convention Center Lower Level, Prince George's Exhibit Hall E
http://www.peregrineinc.com/images/stories/pdfs/sitc_172_gong.pdf (see images below)
[Note: Journal for ImmunoTherapy of Cancer refs Poster #172 as #P151: http://www.immunotherapyofcancer.org/content/1/S1/P151 ]
Poster #176 “Phosphatidylserine-targeting Antibody Induces M1 Macrophage Polarization, Promotes Myeloid Derived Suppressor Cell Differentiation, Boosts Tumor-Specific Immunity”
Xianming Huang, Yin Yi, Gustavo Barbero, Dan Ye, Philip E. Thorpe, Dept. of Pharmacology, The Univ. of Texas SW Medical Center, Dallas, Texas
When: Saturday, Nov. 9th 6:15-7:15 PM
Location: Gaylord National Hotel & Convention Center, Convention Center Lower Level, Prince George's Exhibit Hall E
http://www.peregrineinc.com/images/stories/pdfs/sitc_176_huang.pdf (see images below)
[Note: Journal for ImmunoTherapy of Cancer refs Poster #176 as #P154: http://www.immunotherapyofcancer.org/content/1/S1/P154 ]
About Bavituximab: A Targeted Immunotherapy
Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, causing the tumor to evade immune detection. Bavituximab targets PS and activates the maturation of dendritic cells and cancer-fighting (M1) macrophages leading to the development of cytotoxic T-cells that fight solid tumors through blocking this immunosuppressive PS signal. Bavituximab is the company's lead PS-targeting investigational product and is currently being evaluated in several solid tumor indications, including non-small cell lung cancer, breast cancer, liver cancer and rectal cancer.
About Peregrine Pharmaceuticals
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials focused on the treatment and diagnosis of cancer. The company is pursuing multiple clinical programs in cancer with its lead immunotherapy candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and third-party customers. Additional information about Peregrine can be found at http://www.peregrineinc.com .
Safe Harbor *snip*
Contact: Christopher Keenan or Jay Carlson, Peregrine Pharmaceuticals, (800) 987-8256 info@peregrineinc.com
IMAGES of SITC 2013 POSTER PDF’s
Poster #172 11-9-13 SITC “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses”
Jian Gong, Xianming Huang, Van Nguyen, Richard Archer, Jeff Hutchins, Steven King, Bruce Freimark, Peregrine Pharm., UTSW-MC/Dallas
PDF: http://www.peregrineinc.com/images/stories/pdfs/sitc_172_gong.pdf
Abstract from Journal for ImmunoTherapy of Cancer (P151): http://www.immunotherapyofcancer.org/content/1/S1/P151
Poster #176 11-9-13 SITC “Phosphatidylserine-targeting Antibody Induces M1 Macrophage Polarization, Promotes Myeloid Derived Suppressor Cell Differentiation, Boosts Tumor-Specific Immunity”
Xianming Huang, Yin Yi, Gustavo Barbero, Dan Ye, Philip E. Thorpe, Dept. of Pharmacology, UTSW-MC/Dallas
PDF: http://www.peregrineinc.com/images/stories/pdfs/sitc_176_huang.pdf
Abstract from Journal for ImmunoTherapy of Cancer (P154): http://www.immunotherapyofcancer.org/content/1/S1/P154
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NOTE: Peregrine presented at the 27th annual SITC mtg. in Oct.2012:
Track: Therapeutic Monoclonal Antibodies In Cancer
#176 “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate & Specific Anti-Tumor Responses”
Bruce Freimark 1, Jian Gong 1, Rich Archer 1, Van Nguyen 1, Christopher Hughes 3, Xianming Huang 2, Yi Yin 2, Philip Thorpe 2
1 Preclinical Development, Peregrine Pharmaceuticals, Tustin, CA
2 Pharmacology, Univ. of Texas, SW Medical Center, Dallas, TX
3 Molecular Biology & Biochemistry, Univ. of California, Irvine, CA
2012: http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf
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B. 10-28-13 IASLC/Sydney - PPHM sponsored symposium, “Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies” (Sydney, AUS) – see MLV’s Dr. George Zavoico’s 11-8-13 Sydney recap at the end…
Symposium Overview (Peregrine Pharmaceuticals “Industry Supported Symposia”):
http://files.shareholder.com/downloads/PPHM/1278144473x4927082x699590/55a61634-bdc3-4564-b6a8-3eb6b4985879/WCLC2013%20Peregrine%20Symposia%20Invitation.pdf
10-28-13 Chairman’s Welcome & Program (Dr. Scott J. Antonia, M.D., Ph.D. – H. Lee Moffitt Cancer Center)
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Oct27-30 2013: “IASLC: 15th World Conf. on Lung Cancer”, Sydney Australia
http://www.2013worldlungcancer.org
IASLC – Intl. Association for the Study of Lung Cancer
“Founded in 1972, IASLC is an intl. organization of nearly 3,000 lung cancer specialists, spanning 80 countries. IASLC members work towards developing and promoting the study of etiology, epidemiology, prevention, diagnosis, treatment and all other aspects of lung cancer. IASLC’s mission is to enhance the understanding and education of lung cancer to scientists, members of the medical community and the public. In addition to the biannual meeting, the IASLC publishes the Journal of Thoracic Oncology, a prized resource for medical specialists and scientists who focus on the detection, prevention, diagnosis, and treatment of lung cancer.”
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Monday, Oct.28 2013: 7:00-8:00 CONCURRENT INDUSTRY SUPPORTED SYMPOSIA
• Symposium supported by Celgene: Tackling the Challenges of Squamous Cell NSCLC Patients (Parkside Ballroom A, Level 1)
• Symposium supported by Myriad: Validation of a 46-Gene Expression Signature in Early-Stage Non-Small-Cell Lung Cancer (Parkside 110 A+B, Level 1)
• Symposium supported by Boehringer Ingelheim: Let's Discuss: Optimising Treatment of Advanced NSCLC(Parkside Auditorium , Level 1)
• Symposium supported by Peregrine Pharmaceuticals: “Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies” (Parkside Ballroom B, Level 1)
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PR 10-15-13: “Symposium at IASLC World Conference on Lung Cancer to Highlight Novel Immune Checkpoints Including Peregrine Pharmaceuticals' Bavituximab PS Target”
• Symposium's Lead Presenter Dmitry Gabrilovich, MD, PhD, Accomplished Clinical Immunologist to Be Accompanied by Panel of Key Thought Leaders From Fields of Oncology, Immunology and Lung Cancer
• Peregrine's Lead Product Candidate Bavituximab Represents the First in a New Class of Immunotherapeutics That Targets the Novel PS Upstream Checkpoint
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=797251
TUSTIN, CA 10/15/13: Peregrine Pharmaceuticals (NASDAQ: PPHM) today announced that participants at the International Association for the Study of Lung Cancer's (IASLC) 15th World Conference on Lung Cancer to be held October 27-30, 2013 in Sydney, Australia will discuss novel immunotherapy checkpoint inhibitors including Peregrine's novel target phosphatidylserine (PS). The conference is the world's largest meeting dedicated to lung cancer and other thoracic malignancies and brings together more than 5,000 delegates from across the medical and scientific professional spectrums from more than 100 countries.
The symposium titled: "Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies" will focus on the identification of new immunosuppressive targets in tumors and the potential for improved clinical outcomes through multiple immune checkpoint blockade. The event will take place in Parkside Ballroom B, Conference Level 1 of the Sydney Convention and Exhibition Centre on Monday, October 28th from 7:00-8:00 AM AET. The program for the symposium is as follows:
Moderator: Scott J. Antonia, MD, PhD
Associate Professor in the Department of Interdisciplinary Oncology and the Co-Program Leader of the Immunology Program at the H. Lee Moffitt Cancer Center, Tampa, Florida
PRESENTATIONS:
Dmitry I. Gabrilovich, MD, PhD
Professor in Cancer Research and Program Leader, Translational Tumor Immunology at The Wistar Institute, Philadelphia, Pennsylvania
"Myeloid-Derived Suppressor Cells as Negative Regulator of Immune Responses in Cancer"
Rolf A. Brekken, PhD
Effie Marie Cain Research Scholar in Angiogenesis Research and an Associate Professor, in the Departments of Surgery and Pharmacology at the Hamon Center for Therapeutic Oncology, University of Texas Southwest Medical Center, Dallas, Texas
"Engagement of Phosphatidylserine (PS) by PS-Targeting Antibodies Blocks a Global Immunosuppressive Checkpoint in the Tumor Microenvironment Inducing Multiple Downstream Anti-Tumor Response Mechanisms"
David E. Gerber, MD
Associate Professor of Internal Medicine in the Hematology-Oncology Division at the University of Texas Southwestern Medical Center, Dallas, Texas
"Clinical Experience and Prospects with Checkpoint Immunotherapy in Lung Cancer"
Peregrine will also be hosting convention visitors at Exhibit Booth #702.
"This conference brings together thought leaders from all over the world and in particular this symposium will bring together a set of key opinion leaders to focus on the current understanding of tumor immune checkpoints and the therapeutic potential of combining upstream and downstream immune checkpoint blockers. We are pleased that part of this discussion will focus on the recent data validating bavituximab's PS as global immunosuppressive checkpoint," said Kerstin Menander, MD, PhD, Head of Medical Oncology at Peregrine Pharmaceuticals. "Drs. Gabrilovich and Antonia are recognized leaders in the immunotherapy community and we are particularly pleased that they agreed to participate in the symposium. Their insights into new approaches for immunotherapy combination therapy studies will be extremely valuable as we continue to advance our bavituximab program toward its first such clinical trials."
ABOUT THE PRESENTERS
Scott J. Antonia, M.D., Ph.D.
Dr. Antonia is currently the Department Chair & Program Leader of the Thoracic Oncology Department Associate Professor in the Department of Interdisciplinary Oncology and Program Leader of the Immunology Program at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. He is also a Professor of Oncology at the University of South Florida College of Medicine in Tampa. Prior to being named chair of Thoracic Oncology in 2010, he was associate chairman of the Sarcoma Department. He joined the Moffitt Cancer Center in 1994. Dr. Antonia received his M.D. and his Ph.D. in Immunology from the University of Connecticut Health Center in Farmington, Connecticut. In addition, he completed an internal medicine residency at Yale University School of Medicine and pursued additional training at Yale through a medical oncology fellowship and post-doctoral fellowship in Immunobiology. Dr. Antonia's work focuses on translational research. Using his molecular biology and cellular background in the development of immunotherapeutic strategies for the treatment of cancer patients, he has developed strategies designed to thwart the immunosuppressive mechanisms used by tumors to evade T-cell mediated rejection. Dr. Antonia has published papers in several peer-reviewed journals, including Science, Clinical Cancer Research, Current Opinions in Oncology, and Cancer Research.
[ http://www.moffitt.org/research--clinical-trials/individual-researchers/scott-j--antonia-md-phd ]
Dmitry I. Gabrilovich, M.D., Ph.D.
Dr. Gabrilovich is currently the Christopher M. Davis Professor in Cancer Research and Program Leader, Translational Tumor Immunology at The Wistar Institute, Philadelphia, Pennsylvania. The Wistar Institute is the nation's first independent institution devoted to medical research and training and has been designated a National Cancer Institute Cancer Center in basic research. Dr. Gabrilovich's lab is focused on understanding the mechanisms of tumor-associated immunosuppression as well as on the development of new effective cancer immunotherapeutics. Prior to joining Wistar, Dr. Gabrilovich was the Robert Rothman Endowed Chair in Cancer Research and Head, Section of Dendritic Cell Biology at the H. Lee Moffitt Cancer Center in the Department of Immunology and a Professor of Oncologic Sciences and Molecular Medicine at the University of South Florida in Tampa, Florida. Prior to this, Dr. Gabrilovich was a Research Fellow at the Imperial College in London, United Kingdom and at the University of Texas Southwestern Medical Center in Dallas, Texas. Dr. Gabrilovich earned his M.D. from Kabardino-Balkarian State University Medical School in Nalchik, Russia and his Ph.D. in Immunology from the Central Institute of Epidemiology in Moscow. He has over 25 years of experience, extensive knowledge in this field and has more than 180 peer-reviewed publications.
[ http://www.wistar.org/our-science/scientists/dmitry-gabrilovich-md-phd ]
Rolf A. Brekken, Ph.D.
Dr. Brekken is the Effie Marie Cain Research Scholar in Angiogenesis Research and an Associate Professor, in the Departments of Surgery and Pharmacology, a Principal Investigator in the Hamon Center for Therapeutic Oncology Research, and a member of Simmons Comprehensive Cancer Center, University of Texas Southwest Medical Center in Dallas, Texas. Dr. Brekken received his Bachelor of Arts degree from Luther College in Decorah, Iowa and his Ph.D. (Cell and Molecular Biology) from UT Southwestern Graduate School of Biomedical Sciences. He completed his postdoctoral training in the Department of Vascular Biology at the Hope Heart Institute in Seattle, Washington where he studied how the extracellular matrix contributes to vascular function in and growth of tumors. He is an author on over 100 peer reviewed scientific papers and is a senior editor of Cancer Research. Research in the Brekken laboratory is funded by the NCI, the American Cancer Society, the Mary Kay Foundation and CPRIT as well as several biopharmaceutical companies.
[ http://profiles.utsouthwestern.edu/profile/10808/rolf-brekken.html ]
David E. Gerber, M.D.
Dr. Gerber is currently an Associate Professor of Internal Medicine in the Hematology-Oncology Division at the University of Texas Southwestern Medical Center in Dallas, Texas where he joined the faculty in 2007. Dr. Gerber earned his M.D. from Cornell University Medical College in New York, New York, and completed his internship and residency in Internal Medicine at the University of Texas Southwestern Medical Center in Dallas, Texas. He completed his fellowship in medical oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Gerber is board certified in Internal Medicine and Medical Oncology. Dr. Gerber is particularly interested in lung cancer and is highly active in related research. His research has generated over 40 peer-reviewed publications. He has authored two books and 12 book chapters on this topic and his studies have contributed to invitations to lecture both nationally and internationally.
[ http://profiles.utsouthwestern.edu/profile/53487/david-gerber.html ]
This symposium will not be webcast.
ABOUT PEREGRINE PHARMACEUTICALS, INC.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials focused on the treatment and diagnosis of cancer. The company is pursuing multiple clinical programs in cancer with its lead immunotherapy candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and third-party customers. Additional information about Peregrine can be found at http://www.peregrineinc.com
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11-8-13: MLV’s George Zavoico (PhD) recaps 10-28-13/IASLC(Sydney), and gives overview of entire Cancer Immunotherapy landscape (CTLA-4, PD-1, PD-L1, and now Bavi/PS-targeting, “a new late-stage immunomodulating agent on the block”). States, “we now believe the evidence supports inclusion of Bavi into this select group of immune checkpoint inhibitors with blockbuster potential.”…
11-8-13 MLV Update on Peregrine Pharmaceuticals, Inc.
http://www.mlvco.com - George B. Zavoico, PhD
”Bavituximab IS an Immune Checkpoint Inhibitor for the Treatment of Cancer”
SCIENCE/MOA-ORIENTED EXCERPTS…
Last week we attended the 15th World Congress on Lung Cancer (WCLC) in Sydney, Australia [ http://tinyurl.com/mjaweu5 ], to assess an emerging body of evidence that Peregrine Pharmaceuticals' lead phosphatidylserine (PS)-targeting antibody candidate, bavituximab (Bavi), is an immune checkpoint inhibitor. Cancer evades our immune system by mechanisms that are only now being elucidated. It has long been a goal to find drugs that will reveal tumor cells to suppressed immune effector cells, enabling them to identify and eliminate tumor cells without injuring normal cells. Important strides have been made to this end with CTLA-4, PD-1, and PD-L1 blocking antibodies. We now believe the evidence supports inclusion of Bavi into this select group of immune checkpoint inhibitors with blockbuster potential that are beginning to change the standard of care in cancer. We urge investors to examine the evidence and begin building a position in Peregrine if they agree with our assessment...
• Peregrine Pharmaceuticals sponsored a symposium last week at the WCLC in Sydney, Australia, that was entitled "Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies." Compelling evidence was presented that combining immune checkpoint inhibitors with each other or other immunotherapies or even chemotherapies may prove to be synergistic in provoking a more robust anti-tumor immune response.
• The speakers reviewed clinical trial results showing potent and durable responses with the most advanced immune checkpoint inhibitors on the market or in clinical trials, including blocking antibodies to CTLA-4 (ipilimumab, Yervoy®), PD-1 (nivolumab), and PD-L1 (lambrolizumab). A typical pattern of response to these agents is a brief disease flare or enlargement as immune cells infiltrate the tumor, followed by tumor shrinkage and a durable long-term response.
• Evidence was presented that PS, a membrane-associated phospholipid, serves as an immune checkpoint when it is exposed on the surface of tumor cells and endothelial cells of the tumor vasculature. Exposed PS binds to several PS receptors on immune cells, stimulating secretion of immunosuppressive cytokines and preventing maturation and activation of other immune cells, thereby inducing an immunosuppressive microenvironment and enabling immune tolerance of the tumor.
• Preclinical studies have shown that Bavi blocks the PS immune checkpoint, enabling a switch to an immunostimulatory tumor microenvironment and activation of immune effector cells that can eliminate tumor cells. A Phase IIb trial showed that adding Bavi to docetaxel as second line therapy led to an impressive 4.4-month prolongation of median overall survival in patients with non-small cell lung cancer. We expect Peregrine to conduct further preclinical and clinical trials to confirm that Bavi is an immune checkpoint inhibitor and to find the most effective drug combinations in treating cancer.
A NEW LATE-STAGE IMMUNOMODULATING AGENT ON THE BLOCK
At a very basic level, the function of the immune system is to differentiate between an organism’s own, or “self,” cells and invading organisms, cells and pathogens, and anything that is foreign, or “non-self.” More importantly, once anything non-self is identified, the immune system is charged with eliminating it without harming any of an organism’s own cells and tissues and before invading pathogens can seriously incapacitate or kill the host. Since tumor cells undergo mutiple mutations as they transform, they become more non-self than self, enabling the immune system to identify and eliminate them. This happens throughout our lifetime as we are exposed to toxins and radiation that cause potentially transformational mutations. Most of the time, our immune system identifies cells that have undergone these changes and destroys them before they cause any harm.
Numerous signaling molecules and receptor-ligand interactions serve to either stimulate or suppress the effector cells of the immune system, principally natural killer, or NK, cells, cytotoxic CD8+ T cells, and a M1-type macrophages, responsible for killing and eliminating anything that is non-self. The immune system must also keep these effector cells in check, preventing them from becoming mistakenly stimulated and harming normal cells. To be absolutely certain that effector cells attack only non-self targets, the immune system evolved multiple checkpoints that, in the simplest terms, serve as go/no-go decision points to either stimulate or suppress the immune response. The consequences of poorly regulated immune checkpoints are autoimmune diseases and cancer. In the former, the immune system mistakes self for non-self (the “go” decision prevails) and begins attacking normal cells. The maintenance of self-tolerance is effectively lost. In the latter, the immune system mistakes non-self for self (the “no-go decision prevails) and enables tumors to proliferate and grow. Tolerance of tumor cells is achieved.
Chemotherapy, both of the traditional cytotoxic and more recently developed targeted types, seek vulnerabilities in the mechanisms that drive proliferation and metastases. Cytotoxic chemotherapy takes advantage of more rapid proliferation of tumor cells to kill more of them faster than it can kill more slowly proliferating normal cells. A balanced regimen must be followed to prevent or minimize adverse events caused by the elimination of faster proliferating normal cells like hematopoietic cells that make blood cells or epithelial cells of the digestive system that continually replace cells sloughing off the lining of the gut. Targeted therapy takes advantage of the observation that certain tumor types are driven to proliferate by a key mutation. Selectively inhibiting that mutated driver protein may put the brake on proliferation, at least until another driver mutation emerges to cause relapse. More often than not, and especially in later stage cancers, chemotherapy is only temporarily effective. The goal of beating cancer with long term durable, if not curative, responses drives investigators and drug developers to understand the biochemical mechanisms enabling tumor cells to suppress the immune system. Cancer vaccines have largely been disappointing thus far, probably because effector cells that may have been stimulated by a cancer antigen or antigens are suppressed when they enter the tumor microenvironment. Pharmacologic inhibition of tumor immunosuppressive mechanisms and restoring the ability of the immune system to recognize tumor cells as non-self and then to eliminate them has the potential of being curative, much more so than chemotherapy or radiation.
Immune Checkpoints and Immunosuppression
It is important to understand that the immune system evolved multiple immune checkpoints, each of which may contribute to the inability of the immune system to identify and eliminate tumor cells. A corollary is that tumors may depend on abnormally regulating more than one immune checkpoint to be able to effectively evade the immune system’s surveillance and response. As mentioned above, immune checkpoints are decision points that determine whether the immune response should proceed with the activation of effector cells, or should be suppressed without activating any effector cells. In effect, each immune checkpoint asks: Is this dangerous to my host? If the answer is “yes,” then the immune response can proceed to the next checkpoint. If “no,” then the immune response is inhibited and tolerance ensues.
An immune checkpoint consists of a receptor and a ligand, typically between two immune cells or between an immune cell and a tumor cell. The ligand may also be a soluble mediator. In effect, there are two competing signaling pathways through these multiple receptorligand interactions, one that stimulates and the other that suppresses activation of regulatory and effector cells. Depending on the balance between competing signals, immune cells will also secrete different mediators, including cytokines, growth factors, lipid-derived mediators such as prostaglandin E2 (PGE2), adenosine, and others, to establish an immunostimulatory or immunosuppressive microenvironment in the tumor.
Briefly, there are 3 key steps in the generation of an anti-tumor immune response: First, dendritic cells process tumor cell-derived antigens and serve as antigen-presenting cells (APCs) by displaying them on their surface on major histocompatibilty complex (MHC) class I or II, but only if they also receive a costimulatory signal. Second, the dendritic cells migrate to lymph nodes where they must activate T cells and NK cells. Finally, activated, tumor antigen specific T cells migrate back to the tumor where they should be able to kill tumor cells, but only if the tumor microenvironment is not immunosuppressive. While there are checkpoints at each one of these steps in the immune response, the last step, when activated effector cells actually confront tumor cells, they can be prevented from killing tumor cells because tumors are very adept at maintaining an immunosuppressive microenvironment, particularly in more hypoxic regions of the tumor:
• Tumors can attract progenitor cells from the bone marrow that differentiate into myeloid-derived suppressor cells (MDSC) that secrete immunosuppressive cytokines (e.g. IL-10, TGF-B).
• These cytokines attract immunosuppressive regulatory T cells (Treg) and suppress CD4+ helper and CD8+ cytotoxic T cell and NK cell immune responses.
• MDSCs can differentiate into tumor-associated macrophages (TAMs) of the M2 type (M2o) and into dendritic cells that remain immature and cannot serve as APCs. Notably, the presence of M2o in tumors correlates with a poor prognosis.
In our view, with a better understanding of immune checkpopints and how tumors maintain an immunosuppressive environment, there are now far more opportunities to explore the development of checkpoint inhibitors in an effort to restore the ability of the immune system to recognize, attack, and kill tumor cells. Some of this work has already come to fruition. Blocking monoclonal antibody drug candidates to CTLA-4 (cytotoxic T cell associated antigen-4), PD-1 (programmed death-1 receptor), and PD-L1 (programmed death-1 receptor ligand) have have demonstrated efficacy in heavily pretreated patients.
CTLA-4, PD-1, and PD-L1
Three immune checkpoint inhibitor targets, CTLA-4, PD-1, and PDL1, have recently been the focus of research and blocking antibodies have been developed for each one. An anti-CTLA-4 antibody, called ipilimumab, has already been approved and is marketed as Yervoy for the treatment of unresectable or metastatic melanoma. Blocking antibodies to PD-1 and PD-L1 are in various stages of clinical development for different cancers. Bristol-Myers Squibb’s (NYSE:BMY, not covered) nivolumab (formerly BMS-936558 and MDX-1106) and Merck & Co.’s (NYSE:MRK, not covered) lambrolizumab (formerly MK-3475) are anti-PD-1 antibodies now in multiple Phase I through III clinical trials. Bristol-Myers Squibb’s BMS-936559 (also called MDX-1105) is an anti-PD-L1 antibody in Phase I trials.
CTLA-4. CTLA-4 is expressed on activated CD4+ T helper cells. Its ligand, or counter-receptor, on APCs is CD80 or CD86 (also called B7- 1 and B7-2, respectively). T helper cells bind to APCs presenting tumor antigens on their MHC class II via their T cell receptor (TCR). However, a co-stimulatory signal must also be received by the T cell in order to be activated, and this signal is mediated by a binding interaction between CD80/86 on the APC and CD28, another recptor, on the T helper cell (this is the “go” switch). Once the T helper cell it activated, it proliferates and begins to secrete immunostimulatory cytokines that help promote the proliferation and activation of other immune cells, including CD8+ cytotoxic T cells and dendrtitic cells. This is an amplification process that helps generate a robust immune response.
Following activation, T helper cells begin to upregulate expression of CTLA-4, which competes with CD28 for binding to CD80/86, eventually displacing it due to its much higher affinity. While CD28 sends an activating signal to T helper cells, CTLA-4 sends an inhibitory, suppressive signal (this is the “no-go” switch). In effect, CTLA-4 serves as a self-limiting signal to the T helper cells. It is considered a strong negative regulator of T cell activation. The T helper cells shut down and the immune response is suppressed. A blocking antibody, such as ipilimumab, prevents the interaction of CTLA-4 with CD80/86, prolonging the immunostimulatory effects by maintaining the CD28-CD80/CD86 binding and T helper cell activation.
Ipilimumab was administered to patients with relapsed/refractory metastatic melanoma and a substantial survival benefit of 3.7 months (10.1 vs. 6.4 months in the active vs. control arms, respectively) was observed. Of particular interest is the durable responses seen with ipilimumab, with a near doubling of patient survival one and two years after treatment (one- and two-year survival rates were 46% and 24%, respectively, in the ipilimumab group versus 25% and 14% in the control group).
The ipilimumab trials were the first Phase III trials to demonstrate a substantial survival benefit with an immune checkpoint inhibitor. In this trial, clinically meaningful survival benefits were observed in patients who would otherwise be at the terminal stage of their melanoma. However, ipilimumab is associated with serious adverse events. Up to 23% or treated patients developed Grade 3 or 4 colitis and hypophysitis (inflammation of the colon and pituitary gland, respectively).
PD-1 and PD-L1. PD-1 is expressed on activated T cells, and it’s ligand, or counter-receptor, PD-L1, is expressed on APCs and tumor cells. Melanoma, glioblastoma, and ovarian, renal, and hepatocellular cancers are associated with elevated expresion of PD-L1. Like CTLA-4 binding to CD80/86, the binding of PD-1 to PD-L1 is an immunosuppressive signal that prevents T cell-mediated killing just as the T cell finds its target. In a Phase I study, the response rate to various doses of nivolumab were 18%, 28%, and 27% in patients with advanced non-small cell lung cancer, melanoma, and renal cell cancer, respectively. Responses were durable, with 65% of patients having a response lasting one year or more. A Phase I trial of BMS-935559 in patients with various advanced cancers showed that PD-L1 blockade produced an objective response rate of 6-17% (depending on the cancer), with prolonged, durable stabilization of disease after 24 weeks of treatment in 12-41% of patients.
Taken together, these results generated quite a lot of excitement, particularly since patients treated in these trials had advanced disease and were heavily pretreated. Most likely, many of the long term responders would likely have died much sooner if they had not been treated with these immune checkpoint inhibitors.
CTLA-4/CD28 and the PD-1/PD-L1 receptor-ligand pairs are just two of many receptor-ligand pairs that could serve as immune checkpoints. Several others are being studied that may also provide clinical benefit if specific blockers are developed. Without any context the following looks like an alphanumeric soup, but several potential immune checkpoint targets are the following receptorligand pairs: HVEM/BTLA, MHC Class I or II and KIR or LAG3, GAL9/TIM3, and others. Blocking antibodies for some of these are already in clincal trials.
Immune Checkpoint Inhibitor Combinations
Due to the complexity and multiple interactions in the propagation of the immune response, it is possible that a combination of two or more immune checkpoint inhibitors may be synergistic in inducing a more robust anti-tumor immune response. This has already been tested in at least one Phase I clinical trial. Nivolumab and ipilimumab were evaluated in patients with advanced melanoma. The 2 drugs were administered concurrently or in sequence, with dose escalation. At all doses, the objective response rate in the concurrent and sequential dosing regimens were 40% and 20%, respectively. At the highest tolerated doses, with the drugs given concurrently, 53% of patients had an objective response, all with a tumor reduction of 80% or more. The investigators concluded that the safety and efficacy demonstrated in this trial was distinct from historical results. With a wide variety of immune checkpont inhibitors in development, the number of possible combinations is almost limitless.
Bavituximab is an Immune Checkpoint Inhibitor
In the simplest terms, an immune checkpoint inhibitor prevents the interaction between a receptor-ligand pair that, when bound together, transduces an immunosuppressive signal that leads to tolerance. Does Peregrine’s bavituximab fulfill this criteria? Peregrine’s bavituximab is an antibody that targets a cell membrane associated phospholipid called phosphatidylserine, or PS. Normally, PS is sequestered on the inside leaflet of the cell membrane. A clue that PS may be an immune checkpoint is the appearance of PS on the outside of cells normal cells dying by apoptosis. A considerable amount of cells in our bodies die and are replaced every day. To prevent an inflammatory or immune response from being triggered every time a normal cell dies by apoptosis and leaves cellular debris in its place, there must be a signal to the immune system that this is not an event that threatens the organism. Instead, phagocytes clean up the debris without any inflammatory response. It turns out that the principal immunosuppressive signal in this series of events is PS. A number of PS receptors on immune cells, including M2os, stimulate the production and secretion of immunosuppressive cytokines, mainly TGF-B and IL-10, when bound to PS. Transformation into M1os and dendritic cell maturation is inhibited and effector T cells remain quiescent.
There is a growing body of evidence that tumors have hijacked this mechanism to elude the immune system. Many tumor cell types, as well as the vascular endothelium of tumor blood vessels have been shown to express PS on their surface. The mix of immunosuppressive cytokines in the tumor appears to prevent not only immune cell activation in the tumor, but also to inhibit any activated immune cells that venture into the tumor microenvironment. Since PS on the surface of tumor cells promotes the establishment of an immunosuppressive microenvironment in tumors, we think it can be considered as an immune checkpoint.
In an animal (mouse) model of cancer, Peregrine discovered that bavituximab, in combination with docetaxel, induced a switch from an immunosuppressive to an immunostimulatory tumor microenvironment. In particular, the drug combination induced the transformation of TAMs from immunosuppressive M2os to immunostimulatory and tumoricidal M1os, along with concomittent changes in the cytokine balance within the tumor, depletion of MDSCs, and an increase in functional, mature dendritic cells. Interestingly, docetaxel amplified the response of the mouse equivalent of bavituximab, 2aG4, as it was shown to increase the expression PS on the surface of cells in the tumor enabling more PS bavituximab interactions. Both 2aG4 and docetaxel alone inhibited tumor growth to some extent, but the combination completely inhibited tumor growth in this mouse model.
Bavituximab induces a switch to an immunostimulatory microenvironment in 2 ways. First, it removes the immunosuppressive signals transduced by PS interacting with its receptors on immune cells and, second, by engaging immunostimulatory Fc? receptors on immune cells by their binding to the Fc region of bavituximab. This stimulates the secretion of pro-inflammatory cytokines, mainly IL-12 and TNF-a, maturation of dendritic cells, and a phenotypic switch from M2 to M1os. The maturation of dendritic cells enables these cells to present tumor-associated antigens and activate cytotoxic CD8+ T cells. Tumor cells are killed by M1os by antibody dependent cell-mediated cytotoxicity (ADCC) as bavituximab binds to PS on the surface of tumor cells and by cytotoxic CD8+ T cells that recognize tumor antigens expressed on the surface of tumor cells.
Bavituximab, ipilimumab, nivolumab/lambrolizumab
Each one of these immune checkpoint inhibitors acts at a different point along the immunostimulatory cascade. Ipilimumab interferes with an inhibitory signal, CTLA-4, directed against cytotoxic T cells when tumor-associated antigens are presented to the T cells by mature dendritic cells. Nivolumab and lambrolizumab interfere downstream of ipilimumab by interfering with an inhibitory signal expressed by PD-L1 on tumor cells that bind to PD-1 on activated T cells just as the T cells identify and get ready to kill the tumor cell. Bavituximab acts upstream of these checkpoint inhibitors, blocking a PS-mediated signal that helps establish an immunosuppressive microenvironment in the tumor.
The different mechanisms of action raises the very interesting prospect of evaluating bavituximab in combination with the other immune checkpoint inhibitors (and perhaps with docetaxel as well) to determine if the anti-tumor immune response is enhanced. Peregrine has previously stated that it is commencing a number of preclinical studies to explore new drug combinations. We look forward to the results of these studies.
With regard to developing a bavituximab-docetaxel combination, Peregrine has guided to commencing a registrational Phase III trial of bavituximab with and without docetaxel as 2nd-Line therapy in non-small cell lung cancer (NSCLC) before year-end. This trial, to be called SUNRISE (Stimulating ImmUne RespoNse thRough BavItuximab in a PhaSE III Lung Cancer), is essentially of the same design as the recently completed Phase IIb trial in the same indication, except with more patients (targeting about 600) and involving more clinical sites (more than 100). Peregrine guides to a 2-year enrollment period and a 1-year follow-up. If the trial starts this year, top line results could be announced before the end of 2017. . .
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BULLETS (Zavoico/MLV 11-8-13 – scattered thru left margin):
• The immune system is carefully regulated to avoid harming normal, healthy cells of an organism while eliminating potentially dangerous invading pathogens and mutated cells that could turn cancerous
• Immune checkpoints, typically receptor-ligand pairs between interacting immune cells and target cells, help differentiate between cells and pathogens that should be eliminated and those that should not
• Tumors establish an immunosuppressive microenvironment that prevents the immune system from becoming activated and eliminating tumor cells
• Restoring the ability of the immune system to identify and eliminate tumor cells is the objective of cancer immunotherapy, including immune checkpoint inhibitors
• Immune checkpoint inhibitors are thought to tip the balance from an immunosuppressive to an immunostimulatory microenvironment in tumors
• Immunosuppressive and immunostimulatory tumor microenvironments are differentiated by the presence of specific types of immune cells and mix of secreted cytokines
• Blocking antibodies to the immune checkpoints CTLA-4, PD-1, and PD-L1 have demonstrated efficacy and durable responses in multiple clinical trials, validating this targeted approach
• Ipilimumab (BMS’ Yervoy), an anti-CTLA-4 antibody, is the first immune checkpoint inhibitor to be approved by the FDA
• Promising clinical trial results have been reported with blocking antibodies to PD-1 and PD-L1, another immune checkpoint
• With so many different immune checkpoints, the question arises whether blocking more than one immune checkpoint with drug combinations may provoke a stronger anti-tumor response with superior efficacy and more durable responses than blocking just one immune checkpoint
• Based on intriguing preclinical studies, bavituximab is emerging as a novel and effective immune checkpoint inhibitor with a unique mechanism of action
• PS is an immune checkpoint based on its ability to interact with receptors on immune cells that lead to the establishment of an immunosuppressive microenvironment
• Bavituximab appears to induce a switch from an immunosuppressive to an immunostimulatory environment in tumors partly by inducing tumor-associated macrophages to switch to a tumoricidal phenotype
• In a Phase IIb trial, adding bavituximab to docetaxel as second line therapy in patients with NSCLC prolonged mOS by 4.4 mos., from 7.3 mos. in the control arm to 11.7 mos. in the drug combination arm
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Ann-Marie Baird (PhD) IASLC TWEETS: https://mobile.twitter.com/BairdAM
https://www.iaslc.org/fellowship/past-winners/anne-marie-baird
A. 11-9-13: 2 Peregrine Posters at SITC/Wash - both on the blockage of PS-mediated immunosuppressive checkpoints by PS-Targeting antibodies. “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."
B. 10-28-13 IASLC/Sydney - PPHM sponsored symposium, “Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies” (Sydney, AUS) – see MLV’s Dr. George Zavoico’s 11-8-13 Sydney recap at the end.
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A. 11-9-13: 2 Peregrine Posters at SITC/Wash - both on the blockage of PS-mediated immunosuppressive checkpoints by PS-Targeting antibodies (incl. Bavituximab) – Abstracts & Images of Poster PDF’s below…
SITC = Society for Immunotherapy of Cancer
Nov7-10 2013 “28th Annual Meeting of the Society for Immunotherapy of Cancer (SITC)”, WashDC
“The yearly SITC Annual Meeting & Associated Programs serve as the primary SITC organized events and the premier destination for scientific exchange, education, and networking in the cancer immunotherapy community… By bringing together over 800 domestic & intl. basic, clinical, and translational scientists from academia, gov’t, and the biotech/pharmaceutical industry, in an interactive, educational environment, SITC's scientific programming helps bridge the "bench to bedside" gap between translational research, development, and clinical practice.”
http://www.sitcancer.org/2013
Schd: SITC: http://www.sitcancer.org/2013/annual-meeting/schedule
Abstracts: http://www.immunotherapyofcancer.org/supplements/1/S1/all
... Journal for ImmunoTherapy of Cancer 2013, (Suppl1 (7Nov2013)
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Peregrine’s 2 Posters:
Poster #172 (P151) “Targeting of Phosphatidylserine by Monoclonal Antibodies Reverses an Immunosuppressive Checkpoint Inducing Innate and Specific Anti-Tumor Responses”
Jian Gong, Rich Archer, Van Nguyen, Jeff Hutchins, Bruce Freimark (Peregrine)
ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed on tumor vascular endothelial cells (ECs) and tumor cells, and exposure is enhanced in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. PS exposure in tumors promotes an immunosuppressive microenvironment which includes the recruitment of myeloid derived suppressor cells (MDSCs) and M2-like macrophages as well as the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumors and their secreted microparticles triggers a Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses this immunosuppressive, PS meditated checkpoint thereby enhancing anti-tumor immunity. A chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using syngeneic tumors and human tumor xenografts in mice, we demonstrate PS targeting antibodies specifically localize to PS exposed on membranes of tumor blood vessels, tumors, tumor-infiltrating inflammatory cells and microparticles. Analysis of blood, spleens and tumor tissue demonstrates that PS targeting antibodies are capable of suppressing tumor growth in multiple tumor types by several mechanisms including destruction of tumor blood vessels by ADCC mechanisms, blockage of the PS-mediated immunosuppressive checkpoint, and reactivation of M1 macrophages, dendritic cell maturation and T-cell cellular anti-tumor responses. The combination of these mechanisms promotes strong localized anti-tumor responses without the side-effects of systemic immune activation.
http://www.immunotherapyofcancer.org/content/1/S1/P151
Poster #176 (P154) ”Phosphatidylserine-targeting Antibody Induces M1 Macrophage Polarization, Promotes Myeloid Derived Suppressor Cell Differentiation and Boosts Tumor-Specific Immunity”
Xianming Huang, Yi Yin, Dan Ye, Rolf Brekken, Philip Thorpe (UTSW)
ABSTRACT: Phosphatidylserine (PS) is a potent immunosuppressive lipid typically segregated to the inner leaflet of the plasma membrane. PS is externalized on tumor vasculature, tumor-derived exosomes, and tumor cells in the tumor microenvironment and externalization is markedly enhanced by therapy (e.g., radiation, chemotherapy, and/or androgen deprivation). Externalized PS interacts with immune cells where it actively promotes immunosuppression and tumor progression by expansion of myeloid derived suppressor cells (MDSCs) and M2-like tumor associated macrophages (TAMs). Bavituximab is a PS-targeting antibody that is being evaluated in multiple late-stage clinical trials in cancer patients. Here we show that treatment of PC3 tumor-bearing mice with 2aG4, a murine-version of bavituximab, significantly depleted M2-likeTAMs and MDSCs and increased the presence of M1-like TAMs and mature dendritic cells. In addition, PS blockade markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. Furthermore, in the immune-competent TRAMP mouse prostate tumor model, combination treatment of anti-PS antibody with castration induced strong tumor-specific T-cell immunity that resulted in significantly improved tumor free long-term survival and apparent cures in 35% of the animals, compared to no long-term survivors in groups treated with either single agent. In vitro studies confirmed that anti-PS re-polarized TAMs from an M2 to M1-like phenotype and drove MDSCs to differentiate into M1-like macrophages and functional dendritic cells. These data suggest that PS expression on the external cell surface defines an upstream immune checkpoint that is primarily responsible for expansion of MDSCs and M2-like TAMs in tumors. The results further support that blockade of the PS signal by bavituximab treatment can reverse this immune checkpoint suppression and promote therapeutically effective anti-tumor immunity.
http://www.immunotherapyofcancer.org/content/1/S1/P154
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11-8-13 Peregrine Press Release about SITC 2013:
Data Presentation at Society for Immunotherapy of Cancer (SITC) Annual Meeting Supports Potential of Peregrine Pharmaceuticals' Novel Immunotherapy Bavituximab in Combination with Anti-CTLA-4 Antibodies
• Phosphatidylserine (PS) and CTLA-4 Targeting Antibody Combination Stopped Tumor Growth in 100% of Animals in Preclinical Melanoma Model
• Planning Underway for Near-Term Phase I Clinical Trial Evaluating Bavituximab and Anti-CTLA-4 Combination Immunotherapy in Patients With Advanced Melanoma
TUSTIN, 11/08/13: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) today announced the presentation of data at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, Maryland being held November 7-10. The data showed that phosphatidylserine (PS)-targeting antibodies reactivate tumor immunity at multiple levels and that these antibodies, when combined with an anti-CTLA-4 antibody, an FDA-approved immunotherapy, yielded enhanced anti-tumor activity in a pre-clinical model of melanoma. Peregrine is planning to initiate a Phase III clinical trial in second-line non-small cell lung cancer with its lead PS-targeting antibody bavituximab by year-end.
In the presentation [#172/P151] titled: "Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses," scientists from Peregrine and The University of Texas Southwestern Medical Center examined the anti-tumor response of a PS-targeting antibody equivalent to bavituximab and anti-CTLA-4 combination therapy in a mouse melanoma model. Results showed that the group (n=12) that received the combination resulted in superior tumor growth inhibition than with either antibody alone with no additional toxicity following multiple treatment doses. In addition, histopathological analysis showed the combination produced more inflammatory cell infiltration and tumor destruction than anti-CTLA-4 alone.
"The results presented at SITC demonstrate that PS-targeting antibodies can block PS-mediated immunosuppression while simultaneously activating the immune system and that these effects can greatly improve the number of subjects responding to anti-CTLA-4 immunotherapy," said Jeff T. Hutchins, Ph.D., Vice President of Preclinical Research at Peregrine. "We believe the encouraging preclinical combination treatment data are due in part to the ability of bavituximab to facilitate an increase in tumor-specific cytotoxic T-cell activity, a function that appears to expand and broaden the potential of immunotherapeutic agents including anti-CTLA-4 and anti-PD-1 which prime and sustain T-cell mediated killing of tumor cells in our pre-clinical models. We are continuing to explore these and other immunotherapy combinations and look forward to reporting additional results as they become available."
In the presentation [#176/P154] titled: "Phosphatidylserine-targeting antibody induces M1 macrophage polarization, promotes myeloid derived suppressor cell differentiation, boosts tumor-specific immunity," researchers from The University of Texas Southwestern Medical Center showed that equivalents of bavituximab facilitated a tumor-localized decrease in immunosuppressive cytokines and immune cells, while inducing an increase in immunostimulatory cytokines, tumor-fighting M1 macrophages, mature dendritic cells and tumor-specific cytotoxic T-cells.
"These encouraging data further support the potential of giving bavituximab to enhance the potential of other immunotherapies such as anti-CTLA-4 antibodies. Our goal is to now advance this combination into clinical studies as part of our plans to obtain further proof of concept data for novel immunotherapy combinations including bavituximab," said Joseph Shan, MPH, vice president of clinical and regulatory affairs at Peregrine. "Recent clinical data have shown that immunotherapies can enhance tumor-specific T-cell responses resulting in promising survival benefits in some patients. We believe that bavituximab, by breaking immune tolerance in tumors and activating both the innate and adaptive immune system, holds the potential to allow more patients to respond to immunotherapies such as anti-CTLA-4 antibodies that target other checkpoints in the immune cascade. As such, 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 immunotherapy in patients with melanoma."
PRESENTATION DETAILS
Poster #172 “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses”
Jian Gong, Xianming Huang, Van Nguyen, Richard Archer, Jeff Hutchins, Steven King, Bruce Freimark, Peregrine Pharmaceuticals, Inc., Tustin, CA, Univ. of Texas SW Medical Center, Dallas, Texas
When: Saturday, Nov. 9th 6:15-7:15 PM
Location: Gaylord National Hotel & Convention Center, Convention Center Lower Level, Prince George's Exhibit Hall E
http://www.peregrineinc.com/images/stories/pdfs/sitc_172_gong.pdf (see images below)
[Note: Journal for ImmunoTherapy of Cancer refs Poster #172 as #P151: http://www.immunotherapyofcancer.org/content/1/S1/P151 ]
Poster #176 “Phosphatidylserine-targeting Antibody Induces M1 Macrophage Polarization, Promotes Myeloid Derived Suppressor Cell Differentiation, Boosts Tumor-Specific Immunity”
Xianming Huang, Yin Yi, Gustavo Barbero, Dan Ye, Philip E. Thorpe, Dept. of Pharmacology, The Univ. of Texas SW Medical Center, Dallas, Texas
When: Saturday, Nov. 9th 6:15-7:15 PM
Location: Gaylord National Hotel & Convention Center, Convention Center Lower Level, Prince George's Exhibit Hall E
http://www.peregrineinc.com/images/stories/pdfs/sitc_176_huang.pdf (see images below)
[Note: Journal for ImmunoTherapy of Cancer refs Poster #176 as #P154: http://www.immunotherapyofcancer.org/content/1/S1/P154 ]
About Bavituximab: A Targeted Immunotherapy
Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, causing the tumor to evade immune detection. Bavituximab targets PS and activates the maturation of dendritic cells and cancer-fighting (M1) macrophages leading to the development of cytotoxic T-cells that fight solid tumors through blocking this immunosuppressive PS signal. Bavituximab is the company's lead PS-targeting investigational product and is currently being evaluated in several solid tumor indications, including non-small cell lung cancer, breast cancer, liver cancer and rectal cancer.
About Peregrine Pharmaceuticals
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials focused on the treatment and diagnosis of cancer. The company is pursuing multiple clinical programs in cancer with its lead immunotherapy candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and third-party customers. Additional information about Peregrine can be found at http://www.peregrineinc.com .
Safe Harbor *snip*
Contact: Christopher Keenan or Jay Carlson, Peregrine Pharmaceuticals, (800) 987-8256 info@peregrineinc.com
IMAGES of SITC 2013 POSTER PDF’s
Poster #172 11-9-13 SITC “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses”
Jian Gong, Xianming Huang, Van Nguyen, Richard Archer, Jeff Hutchins, Steven King, Bruce Freimark, Peregrine Pharm., UTSW-MC/Dallas
PDF: http://www.peregrineinc.com/images/stories/pdfs/sitc_172_gong.pdf
Abstract from Journal for ImmunoTherapy of Cancer (P151): http://www.immunotherapyofcancer.org/content/1/S1/P151
Poster #176 11-9-13 SITC “Phosphatidylserine-targeting Antibody Induces M1 Macrophage Polarization, Promotes Myeloid Derived Suppressor Cell Differentiation, Boosts Tumor-Specific Immunity”
Xianming Huang, Yin Yi, Gustavo Barbero, Dan Ye, Philip E. Thorpe, Dept. of Pharmacology, UTSW-MC/Dallas
PDF: http://www.peregrineinc.com/images/stories/pdfs/sitc_176_huang.pdf
Abstract from Journal for ImmunoTherapy of Cancer (P154): http://www.immunotherapyofcancer.org/content/1/S1/P154
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NOTE: Peregrine presented at the 27th annual SITC mtg. in Oct.2012:
Track: Therapeutic Monoclonal Antibodies In Cancer
#176 “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate & Specific Anti-Tumor Responses”
Bruce Freimark 1, Jian Gong 1, Rich Archer 1, Van Nguyen 1, Christopher Hughes 3, Xianming Huang 2, Yi Yin 2, Philip Thorpe 2
1 Preclinical Development, Peregrine Pharmaceuticals, Tustin, CA
2 Pharmacology, Univ. of Texas, SW Medical Center, Dallas, TX
3 Molecular Biology & Biochemistry, Univ. of California, Irvine, CA
2012: http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf
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B. 10-28-13 IASLC/Sydney - PPHM sponsored symposium, “Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies” (Sydney, AUS) – see MLV’s Dr. George Zavoico’s 11-8-13 Sydney recap at the end…
Symposium Overview (Peregrine Pharmaceuticals “Industry Supported Symposia”):
http://files.shareholder.com/downloads/PPHM/1278144473x4927082x699590/55a61634-bdc3-4564-b6a8-3eb6b4985879/WCLC2013%20Peregrine%20Symposia%20Invitation.pdf
10-28-13 Chairman’s Welcome & Program (Dr. Scott J. Antonia, M.D., Ph.D. – H. Lee Moffitt Cancer Center)
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Oct27-30 2013: “IASLC: 15th World Conf. on Lung Cancer”, Sydney Australia
http://www.2013worldlungcancer.org
IASLC – Intl. Association for the Study of Lung Cancer
“Founded in 1972, IASLC is an intl. organization of nearly 3,000 lung cancer specialists, spanning 80 countries. IASLC members work towards developing and promoting the study of etiology, epidemiology, prevention, diagnosis, treatment and all other aspects of lung cancer. IASLC’s mission is to enhance the understanding and education of lung cancer to scientists, members of the medical community and the public. In addition to the biannual meeting, the IASLC publishes the Journal of Thoracic Oncology, a prized resource for medical specialists and scientists who focus on the detection, prevention, diagnosis, and treatment of lung cancer.”
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Monday, Oct.28 2013: 7:00-8:00 CONCURRENT INDUSTRY SUPPORTED SYMPOSIA
• Symposium supported by Celgene: Tackling the Challenges of Squamous Cell NSCLC Patients (Parkside Ballroom A, Level 1)
• Symposium supported by Myriad: Validation of a 46-Gene Expression Signature in Early-Stage Non-Small-Cell Lung Cancer (Parkside 110 A+B, Level 1)
• Symposium supported by Boehringer Ingelheim: Let's Discuss: Optimising Treatment of Advanced NSCLC(Parkside Auditorium , Level 1)
• Symposium supported by Peregrine Pharmaceuticals: “Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies” (Parkside Ballroom B, Level 1)
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PR 10-15-13: “Symposium at IASLC World Conference on Lung Cancer to Highlight Novel Immune Checkpoints Including Peregrine Pharmaceuticals' Bavituximab PS Target”
• Symposium's Lead Presenter Dmitry Gabrilovich, MD, PhD, Accomplished Clinical Immunologist to Be Accompanied by Panel of Key Thought Leaders From Fields of Oncology, Immunology and Lung Cancer
• Peregrine's Lead Product Candidate Bavituximab Represents the First in a New Class of Immunotherapeutics That Targets the Novel PS Upstream Checkpoint
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=797251
TUSTIN, CA 10/15/13: Peregrine Pharmaceuticals (NASDAQ: PPHM) today announced that participants at the International Association for the Study of Lung Cancer's (IASLC) 15th World Conference on Lung Cancer to be held October 27-30, 2013 in Sydney, Australia will discuss novel immunotherapy checkpoint inhibitors including Peregrine's novel target phosphatidylserine (PS). The conference is the world's largest meeting dedicated to lung cancer and other thoracic malignancies and brings together more than 5,000 delegates from across the medical and scientific professional spectrums from more than 100 countries.
The symposium titled: "Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies" will focus on the identification of new immunosuppressive targets in tumors and the potential for improved clinical outcomes through multiple immune checkpoint blockade. The event will take place in Parkside Ballroom B, Conference Level 1 of the Sydney Convention and Exhibition Centre on Monday, October 28th from 7:00-8:00 AM AET. The program for the symposium is as follows:
Moderator: Scott J. Antonia, MD, PhD
Associate Professor in the Department of Interdisciplinary Oncology and the Co-Program Leader of the Immunology Program at the H. Lee Moffitt Cancer Center, Tampa, Florida
PRESENTATIONS:
Dmitry I. Gabrilovich, MD, PhD
Professor in Cancer Research and Program Leader, Translational Tumor Immunology at The Wistar Institute, Philadelphia, Pennsylvania
"Myeloid-Derived Suppressor Cells as Negative Regulator of Immune Responses in Cancer"
Rolf A. Brekken, PhD
Effie Marie Cain Research Scholar in Angiogenesis Research and an Associate Professor, in the Departments of Surgery and Pharmacology at the Hamon Center for Therapeutic Oncology, University of Texas Southwest Medical Center, Dallas, Texas
"Engagement of Phosphatidylserine (PS) by PS-Targeting Antibodies Blocks a Global Immunosuppressive Checkpoint in the Tumor Microenvironment Inducing Multiple Downstream Anti-Tumor Response Mechanisms"
David E. Gerber, MD
Associate Professor of Internal Medicine in the Hematology-Oncology Division at the University of Texas Southwestern Medical Center, Dallas, Texas
"Clinical Experience and Prospects with Checkpoint Immunotherapy in Lung Cancer"
Peregrine will also be hosting convention visitors at Exhibit Booth #702.
"This conference brings together thought leaders from all over the world and in particular this symposium will bring together a set of key opinion leaders to focus on the current understanding of tumor immune checkpoints and the therapeutic potential of combining upstream and downstream immune checkpoint blockers. We are pleased that part of this discussion will focus on the recent data validating bavituximab's PS as global immunosuppressive checkpoint," said Kerstin Menander, MD, PhD, Head of Medical Oncology at Peregrine Pharmaceuticals. "Drs. Gabrilovich and Antonia are recognized leaders in the immunotherapy community and we are particularly pleased that they agreed to participate in the symposium. Their insights into new approaches for immunotherapy combination therapy studies will be extremely valuable as we continue to advance our bavituximab program toward its first such clinical trials."
ABOUT THE PRESENTERS
Scott J. Antonia, M.D., Ph.D.
Dr. Antonia is currently the Department Chair & Program Leader of the Thoracic Oncology Department Associate Professor in the Department of Interdisciplinary Oncology and Program Leader of the Immunology Program at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. He is also a Professor of Oncology at the University of South Florida College of Medicine in Tampa. Prior to being named chair of Thoracic Oncology in 2010, he was associate chairman of the Sarcoma Department. He joined the Moffitt Cancer Center in 1994. Dr. Antonia received his M.D. and his Ph.D. in Immunology from the University of Connecticut Health Center in Farmington, Connecticut. In addition, he completed an internal medicine residency at Yale University School of Medicine and pursued additional training at Yale through a medical oncology fellowship and post-doctoral fellowship in Immunobiology. Dr. Antonia's work focuses on translational research. Using his molecular biology and cellular background in the development of immunotherapeutic strategies for the treatment of cancer patients, he has developed strategies designed to thwart the immunosuppressive mechanisms used by tumors to evade T-cell mediated rejection. Dr. Antonia has published papers in several peer-reviewed journals, including Science, Clinical Cancer Research, Current Opinions in Oncology, and Cancer Research.
[ http://www.moffitt.org/research--clinical-trials/individual-researchers/scott-j--antonia-md-phd ]
Dmitry I. Gabrilovich, M.D., Ph.D.
Dr. Gabrilovich is currently the Christopher M. Davis Professor in Cancer Research and Program Leader, Translational Tumor Immunology at The Wistar Institute, Philadelphia, Pennsylvania. The Wistar Institute is the nation's first independent institution devoted to medical research and training and has been designated a National Cancer Institute Cancer Center in basic research. Dr. Gabrilovich's lab is focused on understanding the mechanisms of tumor-associated immunosuppression as well as on the development of new effective cancer immunotherapeutics. Prior to joining Wistar, Dr. Gabrilovich was the Robert Rothman Endowed Chair in Cancer Research and Head, Section of Dendritic Cell Biology at the H. Lee Moffitt Cancer Center in the Department of Immunology and a Professor of Oncologic Sciences and Molecular Medicine at the University of South Florida in Tampa, Florida. Prior to this, Dr. Gabrilovich was a Research Fellow at the Imperial College in London, United Kingdom and at the University of Texas Southwestern Medical Center in Dallas, Texas. Dr. Gabrilovich earned his M.D. from Kabardino-Balkarian State University Medical School in Nalchik, Russia and his Ph.D. in Immunology from the Central Institute of Epidemiology in Moscow. He has over 25 years of experience, extensive knowledge in this field and has more than 180 peer-reviewed publications.
[ http://www.wistar.org/our-science/scientists/dmitry-gabrilovich-md-phd ]
Rolf A. Brekken, Ph.D.
Dr. Brekken is the Effie Marie Cain Research Scholar in Angiogenesis Research and an Associate Professor, in the Departments of Surgery and Pharmacology, a Principal Investigator in the Hamon Center for Therapeutic Oncology Research, and a member of Simmons Comprehensive Cancer Center, University of Texas Southwest Medical Center in Dallas, Texas. Dr. Brekken received his Bachelor of Arts degree from Luther College in Decorah, Iowa and his Ph.D. (Cell and Molecular Biology) from UT Southwestern Graduate School of Biomedical Sciences. He completed his postdoctoral training in the Department of Vascular Biology at the Hope Heart Institute in Seattle, Washington where he studied how the extracellular matrix contributes to vascular function in and growth of tumors. He is an author on over 100 peer reviewed scientific papers and is a senior editor of Cancer Research. Research in the Brekken laboratory is funded by the NCI, the American Cancer Society, the Mary Kay Foundation and CPRIT as well as several biopharmaceutical companies.
[ http://profiles.utsouthwestern.edu/profile/10808/rolf-brekken.html ]
David E. Gerber, M.D.
Dr. Gerber is currently an Associate Professor of Internal Medicine in the Hematology-Oncology Division at the University of Texas Southwestern Medical Center in Dallas, Texas where he joined the faculty in 2007. Dr. Gerber earned his M.D. from Cornell University Medical College in New York, New York, and completed his internship and residency in Internal Medicine at the University of Texas Southwestern Medical Center in Dallas, Texas. He completed his fellowship in medical oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Gerber is board certified in Internal Medicine and Medical Oncology. Dr. Gerber is particularly interested in lung cancer and is highly active in related research. His research has generated over 40 peer-reviewed publications. He has authored two books and 12 book chapters on this topic and his studies have contributed to invitations to lecture both nationally and internationally.
[ http://profiles.utsouthwestern.edu/profile/53487/david-gerber.html ]
This symposium will not be webcast.
ABOUT PEREGRINE PHARMACEUTICALS, INC.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials focused on the treatment and diagnosis of cancer. The company is pursuing multiple clinical programs in cancer with its lead immunotherapy candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and third-party customers. Additional information about Peregrine can be found at http://www.peregrineinc.com
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11-8-13: MLV’s George Zavoico (PhD) recaps 10-28-13/IASLC(Sydney), and gives overview of entire Cancer Immunotherapy landscape (CTLA-4, PD-1, PD-L1, and now Bavi/PS-targeting, “a new late-stage immunomodulating agent on the block”). States, “we now believe the evidence supports inclusion of Bavi into this select group of immune checkpoint inhibitors with blockbuster potential.”…
11-8-13 MLV Update on Peregrine Pharmaceuticals, Inc.
http://www.mlvco.com - George B. Zavoico, PhD
”Bavituximab IS an Immune Checkpoint Inhibitor for the Treatment of Cancer”
SCIENCE/MOA-ORIENTED EXCERPTS…
Last week we attended the 15th World Congress on Lung Cancer (WCLC) in Sydney, Australia [ http://tinyurl.com/mjaweu5 ], to assess an emerging body of evidence that Peregrine Pharmaceuticals' lead phosphatidylserine (PS)-targeting antibody candidate, bavituximab (Bavi), is an immune checkpoint inhibitor. Cancer evades our immune system by mechanisms that are only now being elucidated. It has long been a goal to find drugs that will reveal tumor cells to suppressed immune effector cells, enabling them to identify and eliminate tumor cells without injuring normal cells. Important strides have been made to this end with CTLA-4, PD-1, and PD-L1 blocking antibodies. We now believe the evidence supports inclusion of Bavi into this select group of immune checkpoint inhibitors with blockbuster potential that are beginning to change the standard of care in cancer. We urge investors to examine the evidence and begin building a position in Peregrine if they agree with our assessment...
• Peregrine Pharmaceuticals sponsored a symposium last week at the WCLC in Sydney, Australia, that was entitled "Immune Checkpoints in the Tumor Environment: Novel Targets and the Clinical Promise of Combined Immunotherapies." Compelling evidence was presented that combining immune checkpoint inhibitors with each other or other immunotherapies or even chemotherapies may prove to be synergistic in provoking a more robust anti-tumor immune response.
• The speakers reviewed clinical trial results showing potent and durable responses with the most advanced immune checkpoint inhibitors on the market or in clinical trials, including blocking antibodies to CTLA-4 (ipilimumab, Yervoy®), PD-1 (nivolumab), and PD-L1 (lambrolizumab). A typical pattern of response to these agents is a brief disease flare or enlargement as immune cells infiltrate the tumor, followed by tumor shrinkage and a durable long-term response.
• Evidence was presented that PS, a membrane-associated phospholipid, serves as an immune checkpoint when it is exposed on the surface of tumor cells and endothelial cells of the tumor vasculature. Exposed PS binds to several PS receptors on immune cells, stimulating secretion of immunosuppressive cytokines and preventing maturation and activation of other immune cells, thereby inducing an immunosuppressive microenvironment and enabling immune tolerance of the tumor.
• Preclinical studies have shown that Bavi blocks the PS immune checkpoint, enabling a switch to an immunostimulatory tumor microenvironment and activation of immune effector cells that can eliminate tumor cells. A Phase IIb trial showed that adding Bavi to docetaxel as second line therapy led to an impressive 4.4-month prolongation of median overall survival in patients with non-small cell lung cancer. We expect Peregrine to conduct further preclinical and clinical trials to confirm that Bavi is an immune checkpoint inhibitor and to find the most effective drug combinations in treating cancer.
A NEW LATE-STAGE IMMUNOMODULATING AGENT ON THE BLOCK
At a very basic level, the function of the immune system is to differentiate between an organism’s own, or “self,” cells and invading organisms, cells and pathogens, and anything that is foreign, or “non-self.” More importantly, once anything non-self is identified, the immune system is charged with eliminating it without harming any of an organism’s own cells and tissues and before invading pathogens can seriously incapacitate or kill the host. Since tumor cells undergo mutiple mutations as they transform, they become more non-self than self, enabling the immune system to identify and eliminate them. This happens throughout our lifetime as we are exposed to toxins and radiation that cause potentially transformational mutations. Most of the time, our immune system identifies cells that have undergone these changes and destroys them before they cause any harm.
Numerous signaling molecules and receptor-ligand interactions serve to either stimulate or suppress the effector cells of the immune system, principally natural killer, or NK, cells, cytotoxic CD8+ T cells, and a M1-type macrophages, responsible for killing and eliminating anything that is non-self. The immune system must also keep these effector cells in check, preventing them from becoming mistakenly stimulated and harming normal cells. To be absolutely certain that effector cells attack only non-self targets, the immune system evolved multiple checkpoints that, in the simplest terms, serve as go/no-go decision points to either stimulate or suppress the immune response. The consequences of poorly regulated immune checkpoints are autoimmune diseases and cancer. In the former, the immune system mistakes self for non-self (the “go” decision prevails) and begins attacking normal cells. The maintenance of self-tolerance is effectively lost. In the latter, the immune system mistakes non-self for self (the “no-go decision prevails) and enables tumors to proliferate and grow. Tolerance of tumor cells is achieved.
Chemotherapy, both of the traditional cytotoxic and more recently developed targeted types, seek vulnerabilities in the mechanisms that drive proliferation and metastases. Cytotoxic chemotherapy takes advantage of more rapid proliferation of tumor cells to kill more of them faster than it can kill more slowly proliferating normal cells. A balanced regimen must be followed to prevent or minimize adverse events caused by the elimination of faster proliferating normal cells like hematopoietic cells that make blood cells or epithelial cells of the digestive system that continually replace cells sloughing off the lining of the gut. Targeted therapy takes advantage of the observation that certain tumor types are driven to proliferate by a key mutation. Selectively inhibiting that mutated driver protein may put the brake on proliferation, at least until another driver mutation emerges to cause relapse. More often than not, and especially in later stage cancers, chemotherapy is only temporarily effective. The goal of beating cancer with long term durable, if not curative, responses drives investigators and drug developers to understand the biochemical mechanisms enabling tumor cells to suppress the immune system. Cancer vaccines have largely been disappointing thus far, probably because effector cells that may have been stimulated by a cancer antigen or antigens are suppressed when they enter the tumor microenvironment. Pharmacologic inhibition of tumor immunosuppressive mechanisms and restoring the ability of the immune system to recognize tumor cells as non-self and then to eliminate them has the potential of being curative, much more so than chemotherapy or radiation.
Immune Checkpoints and Immunosuppression
It is important to understand that the immune system evolved multiple immune checkpoints, each of which may contribute to the inability of the immune system to identify and eliminate tumor cells. A corollary is that tumors may depend on abnormally regulating more than one immune checkpoint to be able to effectively evade the immune system’s surveillance and response. As mentioned above, immune checkpoints are decision points that determine whether the immune response should proceed with the activation of effector cells, or should be suppressed without activating any effector cells. In effect, each immune checkpoint asks: Is this dangerous to my host? If the answer is “yes,” then the immune response can proceed to the next checkpoint. If “no,” then the immune response is inhibited and tolerance ensues.
An immune checkpoint consists of a receptor and a ligand, typically between two immune cells or between an immune cell and a tumor cell. The ligand may also be a soluble mediator. In effect, there are two competing signaling pathways through these multiple receptorligand interactions, one that stimulates and the other that suppresses activation of regulatory and effector cells. Depending on the balance between competing signals, immune cells will also secrete different mediators, including cytokines, growth factors, lipid-derived mediators such as prostaglandin E2 (PGE2), adenosine, and others, to establish an immunostimulatory or immunosuppressive microenvironment in the tumor.
Briefly, there are 3 key steps in the generation of an anti-tumor immune response: First, dendritic cells process tumor cell-derived antigens and serve as antigen-presenting cells (APCs) by displaying them on their surface on major histocompatibilty complex (MHC) class I or II, but only if they also receive a costimulatory signal. Second, the dendritic cells migrate to lymph nodes where they must activate T cells and NK cells. Finally, activated, tumor antigen specific T cells migrate back to the tumor where they should be able to kill tumor cells, but only if the tumor microenvironment is not immunosuppressive. While there are checkpoints at each one of these steps in the immune response, the last step, when activated effector cells actually confront tumor cells, they can be prevented from killing tumor cells because tumors are very adept at maintaining an immunosuppressive microenvironment, particularly in more hypoxic regions of the tumor:
• Tumors can attract progenitor cells from the bone marrow that differentiate into myeloid-derived suppressor cells (MDSC) that secrete immunosuppressive cytokines (e.g. IL-10, TGF-B).
• These cytokines attract immunosuppressive regulatory T cells (Treg) and suppress CD4+ helper and CD8+ cytotoxic T cell and NK cell immune responses.
• MDSCs can differentiate into tumor-associated macrophages (TAMs) of the M2 type (M2o) and into dendritic cells that remain immature and cannot serve as APCs. Notably, the presence of M2o in tumors correlates with a poor prognosis.
In our view, with a better understanding of immune checkpopints and how tumors maintain an immunosuppressive environment, there are now far more opportunities to explore the development of checkpoint inhibitors in an effort to restore the ability of the immune system to recognize, attack, and kill tumor cells. Some of this work has already come to fruition. Blocking monoclonal antibody drug candidates to CTLA-4 (cytotoxic T cell associated antigen-4), PD-1 (programmed death-1 receptor), and PD-L1 (programmed death-1 receptor ligand) have have demonstrated efficacy in heavily pretreated patients.
CTLA-4, PD-1, and PD-L1
Three immune checkpoint inhibitor targets, CTLA-4, PD-1, and PDL1, have recently been the focus of research and blocking antibodies have been developed for each one. An anti-CTLA-4 antibody, called ipilimumab, has already been approved and is marketed as Yervoy for the treatment of unresectable or metastatic melanoma. Blocking antibodies to PD-1 and PD-L1 are in various stages of clinical development for different cancers. Bristol-Myers Squibb’s (NYSE:BMY, not covered) nivolumab (formerly BMS-936558 and MDX-1106) and Merck & Co.’s (NYSE:MRK, not covered) lambrolizumab (formerly MK-3475) are anti-PD-1 antibodies now in multiple Phase I through III clinical trials. Bristol-Myers Squibb’s BMS-936559 (also called MDX-1105) is an anti-PD-L1 antibody in Phase I trials.
CTLA-4. CTLA-4 is expressed on activated CD4+ T helper cells. Its ligand, or counter-receptor, on APCs is CD80 or CD86 (also called B7- 1 and B7-2, respectively). T helper cells bind to APCs presenting tumor antigens on their MHC class II via their T cell receptor (TCR). However, a co-stimulatory signal must also be received by the T cell in order to be activated, and this signal is mediated by a binding interaction between CD80/86 on the APC and CD28, another recptor, on the T helper cell (this is the “go” switch). Once the T helper cell it activated, it proliferates and begins to secrete immunostimulatory cytokines that help promote the proliferation and activation of other immune cells, including CD8+ cytotoxic T cells and dendrtitic cells. This is an amplification process that helps generate a robust immune response.
Following activation, T helper cells begin to upregulate expression of CTLA-4, which competes with CD28 for binding to CD80/86, eventually displacing it due to its much higher affinity. While CD28 sends an activating signal to T helper cells, CTLA-4 sends an inhibitory, suppressive signal (this is the “no-go” switch). In effect, CTLA-4 serves as a self-limiting signal to the T helper cells. It is considered a strong negative regulator of T cell activation. The T helper cells shut down and the immune response is suppressed. A blocking antibody, such as ipilimumab, prevents the interaction of CTLA-4 with CD80/86, prolonging the immunostimulatory effects by maintaining the CD28-CD80/CD86 binding and T helper cell activation.
Ipilimumab was administered to patients with relapsed/refractory metastatic melanoma and a substantial survival benefit of 3.7 months (10.1 vs. 6.4 months in the active vs. control arms, respectively) was observed. Of particular interest is the durable responses seen with ipilimumab, with a near doubling of patient survival one and two years after treatment (one- and two-year survival rates were 46% and 24%, respectively, in the ipilimumab group versus 25% and 14% in the control group).
The ipilimumab trials were the first Phase III trials to demonstrate a substantial survival benefit with an immune checkpoint inhibitor. In this trial, clinically meaningful survival benefits were observed in patients who would otherwise be at the terminal stage of their melanoma. However, ipilimumab is associated with serious adverse events. Up to 23% or treated patients developed Grade 3 or 4 colitis and hypophysitis (inflammation of the colon and pituitary gland, respectively).
PD-1 and PD-L1. PD-1 is expressed on activated T cells, and it’s ligand, or counter-receptor, PD-L1, is expressed on APCs and tumor cells. Melanoma, glioblastoma, and ovarian, renal, and hepatocellular cancers are associated with elevated expresion of PD-L1. Like CTLA-4 binding to CD80/86, the binding of PD-1 to PD-L1 is an immunosuppressive signal that prevents T cell-mediated killing just as the T cell finds its target. In a Phase I study, the response rate to various doses of nivolumab were 18%, 28%, and 27% in patients with advanced non-small cell lung cancer, melanoma, and renal cell cancer, respectively. Responses were durable, with 65% of patients having a response lasting one year or more. A Phase I trial of BMS-935559 in patients with various advanced cancers showed that PD-L1 blockade produced an objective response rate of 6-17% (depending on the cancer), with prolonged, durable stabilization of disease after 24 weeks of treatment in 12-41% of patients.
Taken together, these results generated quite a lot of excitement, particularly since patients treated in these trials had advanced disease and were heavily pretreated. Most likely, many of the long term responders would likely have died much sooner if they had not been treated with these immune checkpoint inhibitors.
CTLA-4/CD28 and the PD-1/PD-L1 receptor-ligand pairs are just two of many receptor-ligand pairs that could serve as immune checkpoints. Several others are being studied that may also provide clinical benefit if specific blockers are developed. Without any context the following looks like an alphanumeric soup, but several potential immune checkpoint targets are the following receptorligand pairs: HVEM/BTLA, MHC Class I or II and KIR or LAG3, GAL9/TIM3, and others. Blocking antibodies for some of these are already in clincal trials.
Immune Checkpoint Inhibitor Combinations
Due to the complexity and multiple interactions in the propagation of the immune response, it is possible that a combination of two or more immune checkpoint inhibitors may be synergistic in inducing a more robust anti-tumor immune response. This has already been tested in at least one Phase I clinical trial. Nivolumab and ipilimumab were evaluated in patients with advanced melanoma. The 2 drugs were administered concurrently or in sequence, with dose escalation. At all doses, the objective response rate in the concurrent and sequential dosing regimens were 40% and 20%, respectively. At the highest tolerated doses, with the drugs given concurrently, 53% of patients had an objective response, all with a tumor reduction of 80% or more. The investigators concluded that the safety and efficacy demonstrated in this trial was distinct from historical results. With a wide variety of immune checkpont inhibitors in development, the number of possible combinations is almost limitless.
Bavituximab is an Immune Checkpoint Inhibitor
In the simplest terms, an immune checkpoint inhibitor prevents the interaction between a receptor-ligand pair that, when bound together, transduces an immunosuppressive signal that leads to tolerance. Does Peregrine’s bavituximab fulfill this criteria? Peregrine’s bavituximab is an antibody that targets a cell membrane associated phospholipid called phosphatidylserine, or PS. Normally, PS is sequestered on the inside leaflet of the cell membrane. A clue that PS may be an immune checkpoint is the appearance of PS on the outside of cells normal cells dying by apoptosis. A considerable amount of cells in our bodies die and are replaced every day. To prevent an inflammatory or immune response from being triggered every time a normal cell dies by apoptosis and leaves cellular debris in its place, there must be a signal to the immune system that this is not an event that threatens the organism. Instead, phagocytes clean up the debris without any inflammatory response. It turns out that the principal immunosuppressive signal in this series of events is PS. A number of PS receptors on immune cells, including M2os, stimulate the production and secretion of immunosuppressive cytokines, mainly TGF-B and IL-10, when bound to PS. Transformation into M1os and dendritic cell maturation is inhibited and effector T cells remain quiescent.
There is a growing body of evidence that tumors have hijacked this mechanism to elude the immune system. Many tumor cell types, as well as the vascular endothelium of tumor blood vessels have been shown to express PS on their surface. The mix of immunosuppressive cytokines in the tumor appears to prevent not only immune cell activation in the tumor, but also to inhibit any activated immune cells that venture into the tumor microenvironment. Since PS on the surface of tumor cells promotes the establishment of an immunosuppressive microenvironment in tumors, we think it can be considered as an immune checkpoint.
In an animal (mouse) model of cancer, Peregrine discovered that bavituximab, in combination with docetaxel, induced a switch from an immunosuppressive to an immunostimulatory tumor microenvironment. In particular, the drug combination induced the transformation of TAMs from immunosuppressive M2os to immunostimulatory and tumoricidal M1os, along with concomittent changes in the cytokine balance within the tumor, depletion of MDSCs, and an increase in functional, mature dendritic cells. Interestingly, docetaxel amplified the response of the mouse equivalent of bavituximab, 2aG4, as it was shown to increase the expression PS on the surface of cells in the tumor enabling more PS bavituximab interactions. Both 2aG4 and docetaxel alone inhibited tumor growth to some extent, but the combination completely inhibited tumor growth in this mouse model.
Bavituximab induces a switch to an immunostimulatory microenvironment in 2 ways. First, it removes the immunosuppressive signals transduced by PS interacting with its receptors on immune cells and, second, by engaging immunostimulatory Fc? receptors on immune cells by their binding to the Fc region of bavituximab. This stimulates the secretion of pro-inflammatory cytokines, mainly IL-12 and TNF-a, maturation of dendritic cells, and a phenotypic switch from M2 to M1os. The maturation of dendritic cells enables these cells to present tumor-associated antigens and activate cytotoxic CD8+ T cells. Tumor cells are killed by M1os by antibody dependent cell-mediated cytotoxicity (ADCC) as bavituximab binds to PS on the surface of tumor cells and by cytotoxic CD8+ T cells that recognize tumor antigens expressed on the surface of tumor cells.
Bavituximab, ipilimumab, nivolumab/lambrolizumab
Each one of these immune checkpoint inhibitors acts at a different point along the immunostimulatory cascade. Ipilimumab interferes with an inhibitory signal, CTLA-4, directed against cytotoxic T cells when tumor-associated antigens are presented to the T cells by mature dendritic cells. Nivolumab and lambrolizumab interfere downstream of ipilimumab by interfering with an inhibitory signal expressed by PD-L1 on tumor cells that bind to PD-1 on activated T cells just as the T cells identify and get ready to kill the tumor cell. Bavituximab acts upstream of these checkpoint inhibitors, blocking a PS-mediated signal that helps establish an immunosuppressive microenvironment in the tumor.
The different mechanisms of action raises the very interesting prospect of evaluating bavituximab in combination with the other immune checkpoint inhibitors (and perhaps with docetaxel as well) to determine if the anti-tumor immune response is enhanced. Peregrine has previously stated that it is commencing a number of preclinical studies to explore new drug combinations. We look forward to the results of these studies.
With regard to developing a bavituximab-docetaxel combination, Peregrine has guided to commencing a registrational Phase III trial of bavituximab with and without docetaxel as 2nd-Line therapy in non-small cell lung cancer (NSCLC) before year-end. This trial, to be called SUNRISE (Stimulating ImmUne RespoNse thRough BavItuximab in a PhaSE III Lung Cancer), is essentially of the same design as the recently completed Phase IIb trial in the same indication, except with more patients (targeting about 600) and involving more clinical sites (more than 100). Peregrine guides to a 2-year enrollment period and a 1-year follow-up. If the trial starts this year, top line results could be announced before the end of 2017. . .
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BULLETS (Zavoico/MLV 11-8-13 – scattered thru left margin):
• The immune system is carefully regulated to avoid harming normal, healthy cells of an organism while eliminating potentially dangerous invading pathogens and mutated cells that could turn cancerous
• Immune checkpoints, typically receptor-ligand pairs between interacting immune cells and target cells, help differentiate between cells and pathogens that should be eliminated and those that should not
• Tumors establish an immunosuppressive microenvironment that prevents the immune system from becoming activated and eliminating tumor cells
• Restoring the ability of the immune system to identify and eliminate tumor cells is the objective of cancer immunotherapy, including immune checkpoint inhibitors
• Immune checkpoint inhibitors are thought to tip the balance from an immunosuppressive to an immunostimulatory microenvironment in tumors
• Immunosuppressive and immunostimulatory tumor microenvironments are differentiated by the presence of specific types of immune cells and mix of secreted cytokines
• Blocking antibodies to the immune checkpoints CTLA-4, PD-1, and PD-L1 have demonstrated efficacy and durable responses in multiple clinical trials, validating this targeted approach
• Ipilimumab (BMS’ Yervoy), an anti-CTLA-4 antibody, is the first immune checkpoint inhibitor to be approved by the FDA
• Promising clinical trial results have been reported with blocking antibodies to PD-1 and PD-L1, another immune checkpoint
• With so many different immune checkpoints, the question arises whether blocking more than one immune checkpoint with drug combinations may provoke a stronger anti-tumor response with superior efficacy and more durable responses than blocking just one immune checkpoint
• Based on intriguing preclinical studies, bavituximab is emerging as a novel and effective immune checkpoint inhibitor with a unique mechanism of action
• PS is an immune checkpoint based on its ability to interact with receptors on immune cells that lead to the establishment of an immunosuppressive microenvironment
• Bavituximab appears to induce a switch from an immunosuppressive to an immunostimulatory environment in tumors partly by inducing tumor-associated macrophages to switch to a tumoricidal phenotype
• In a Phase IIb trial, adding bavituximab to docetaxel as second line therapy in patients with NSCLC prolonged mOS by 4.4 mos., from 7.3 mos. in the control arm to 11.7 mos. in the drug combination arm
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Ann-Marie Baird (PhD) IASLC TWEETS: https://mobile.twitter.com/BairdAM
https://www.iaslc.org/fellowship/past-winners/anne-marie-baird
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