AI
Tuesday, September 08, 2015 12:49:53 PM
Scott Antonia’s (Moffitt CC) 9-8-15 IASLC’15 Mini-Oral Presentation Slideshow (9pgs: Bavi Lung Translational Data) now on PeregrineInc.com, as is UTSW’s Dr. David Gerber’s poster overviewing the ongoing Ph.3 Bavi+Doce 2L/NSCLC “SUNRISE” trial – see below…
(recall, UTSW’s Dr. Rolf Brekken gives an Oral Pres. tomorrow, Sept9, discussing, “previously announced study findings demonstrating that a combination of bavituximab and an anti-PD-1 antibody was more effective at reducing tumor burden in preclinical lung cancer models than either treatment alone.”)
Sept6-9 2015: “IASLC’s 16th World Conf. on Lung Cancer”, Denver
http://wclc2015.iaslc.org/
“The World Conference on Lung Cancer (WCLC) is the world’s largest meeting dedicated to lung cancer and other thoracic malignancies. More than 7,000 delegates come from more than 100 countries to discuss the latest developments in thoracic malignancy research. Attendees include surgeons, medical oncologists, radiation oncologists, pulmonologists, radiologists, pathologists, epidemiologists, basic research scientists, nurses, allied health professionals, advocates, and patients.”
http://www.iaslc.org/events/16th-world-conference-lung-cancer
2015 Exhibitor: Peregrine Pharm. (1 of 39) - booth #1724 (adjacent to Abbvie)
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WCLC 2015 Track: Treatment of Advanced Diseases - NSCLC
9/7/15 9:30am-5:00pm, Exhibit Hall (Hall B+C)
POSTER #P1.01-075: “Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)
David R. Spigel, Joseph Shan, Alberto Chiappori, Ulrich Keilholz, Martin Reck, Martin Edelman, Manuel Domine, Keunchil Park, Tae Won Jang, Wu-Chou Su, Rachel E. Sanborn, Leora Horn, Rebecca Heist, Paul Mainwaring, David E. Gerber (UTSW)
ABSTRACT…
BACKGROUND: Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-B and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-a and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous NSCLC, bavituximab 3 mg/kg + docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 mos) in median overall survival (OS) compared to control.
METHODS: SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in Dec.2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and 2 interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every 2 cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.
RESULTS: Trial in progress
CONCLUSION: Trial in progress
POSTER: http://www.peregrineinc.com/images/stories/pdfs/iaslc_2015_sunrise.pdf
From Peregrine’s 9-8-15 PR:
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=930479
"A large and growing body of research continues to support our belief that, as a fundamental checkpoint inhibitor, bavituximab may have the potential to broadly enhance the therapeutic activity of a range of cancer treatments including chemotherapy, radiation and immunotherapies. These latest data being presented at the World Conference on Lung Cancer specifically highlight this synergistic potential in the area of checkpoint inhibitors by clearly illustrating the manner in which bavituximab is able to induce the appropriate immune responses required for a successful therapeutic response to anti-PD-1 & anti-PD-L1 agents," said Steven W. King, President and CEO of Peregrine. "We look forward to continuing our investigation of bavituximab in combination with other immuno-oncology agents through our ongoing collaborations with AstraZeneca, the Memorial Sloan Kettering Cancer Center and UT Southwestern."
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WCLC 2015 Track: MINI ORAL #14 - Pre-Clinical Therapy (ID 119)
Moderators: Lynnette Fernandez-Cuesta Adi F. Gazdar
9/8/15, 10:45am-12:15pm, Mile High Ballroom 2c-3c
MINI-ORAL #14.07: “Bavituximab Activates CD8+ TILs in a 3D Ex Vivo System of Lung Cancer Patients Derived Tumors With Negative PD-L1 Expression”
Soner Altiok, Melanie Mediavilla Valera, Jenny Kreahling, Nikoletta L. Kallinteris, David Noyes, Tiffany N. Razabdouski, Joseph Shan, Jeff Hutchins, Kerstin Menander, Scott J. Antonia (Moffitt CC)
ABSTRACT…
BACKGROUND: Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Bavituximab blocks PS-mediated immune suppression and activates cytotoxic T lymphocyte anti-tumor responses.
METHODS: Tissues from consented patients with adenocarcinoma of the lung were extracted at the time of surgical resection and disaggregated to characterize expression of immune checkpoint proteins such as PD-1, CTLA-4, LAG3, TIM3, BTLA and adenosine A2A receptor on both CD4+ and CD8+ tumor infiltrating cells by flow cytometry (FACS) and stained for PD-L1, CD68, and CD163 via immunohistochemistry (IHC). 3D tumor microspheres were prepared and treated ex vivo with an IgG control, F(ab)’2 version of bavituximab, bavituximab, docetaxel, anti-PD-1 or PD-L1 and combinations of bavituximab, anti-PD-1 or PD-L1 and docetaxel for 36 hours within an intact tumor microenvironment. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by treatment. In a few cases, the expanded TILs were tested in PDX models using the consented patient’s tumor.
RESULTS: Bavituximab induces activation of TILs in 3D ex vivo tumor microsphere models of lung cancer, as demonstrated by a significant increase in IFN-y, TNF-a, and GM-CSF secretion. FACS, IHC, and NanoString gene function analysis read out assays revealed that this effect was associated with low PD-1 expression on CD8+ cells, negative PD-L1 expression in the stating biopsy tissue, and a conversion of the M2 to M1 macrophage phenotype.
CONCLUSION: These data support the use of bavituximab as an immunomodulatory treatment in adenocarcinoma of the lung by enhancing the activation of CD8+ TIL derived from patients' tumors with negative PD-L1 expression; correlating with increased cytokine production by lymphoid cells and repolarization of myeloid cells from an immunosuppressive to an immune active state.
SLIDESHOW (9 pgs.): http://www.peregrineinc.com/images/stories/pdfs/iaslc_2015_altiok.pdf
From Peregrine’s 9-8-15 PR:
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=930479
”For the study presented at the WCLC, researchers from Nilogen Oncosystems [<=Moffitt Startup: http://otmc.moffitt.org/startups.aspx ] and the H. Lee Moffitt Cancer Center, in collaboration with Peregrine, evaluated immune changes in 3D tumor microspheres generated from human NSCLC fresh tumors extracted at the time of surgery. These were tumor microspheres were treated with bavituximab alone, docetaxel alone, a combination of bavituximab and docetaxel, and a control. Bavituximab, alone and in combination with docetaxel, induced activation of tumor infiltrating lymphocytes as demonstrated by a statistically significant increase in key immune-stimulating cytokines such as IFN-y, TNF-a, and GM-CSF with a corresponding decrease in secretion of the immunosuppressive cytokine IL-10. Importantly, the bavituximab-affected immune response activity appeared to correlate with low PD-L1 expression on the tumor samples. "These new translational data suggest that bavituximab has the potential to activate a tumor specific immune response in patients with PD-L1 negative tumors that generally do not respond as well to immune checkpoint inhibitors. By doing so, it is believed that bavituximab may hold potential to increase the number of patients able to respond to PD-1 & PD-L1 targeting immunotherapies," said Jeff Hutchins, VP, Preclinical Dev. of Peregrine. "These findings continue to expand our collection of translational data supporting the mechanism of action for bavituximab and corroborate our wide range of previously published preclinical study results. Taken together, these data provide us with growing confidence for our bavituximab development programs, including the ongoing Phase III SUNRISE clinical trial in NSCLC which is evaluating the same treatment combination used in these studies."
- - - - - - - - - - - - - - - - - - - - - - -
WCLC 2015 Track: ORAL #41 - Immune Biology, Microenvironment & Novel Targets (ID 159)
Moderators: Sukhmani K. Padda, Raphael Nemenoff
9/9/15, 6:30-8:00pm, Four Seasons Ballroom F1+F2
ORAL #41.05: “Targeting Phosphatidylserine-Mediated Immune Suppression Enhances the Efficacy of Immune Checkpoint Blockade in Pre-Clinical Tumor Models”
Rolf A. Brekken (UTSW), Bruce Freimark, Jian Gong, Carrie Baldwin, Van Nguyen, Michael Gray, Shen Yin, Jeff Hutchins, Alan Schroit, Xianming Huang (UTSW)
ABSTRACT…
BACKGROUND: Despite substantial progress, only a subset of cancer patients benefit from blockade of the PD-1 immune checkpoint. Multifocal immune suppression in the tumor microenvironment is the underlying cause for the limited efficacy of immune checkpoint blockade. Persistent immune suppression prevents the development of a robust T cell response to tumor specific antigens that is required for effective downstream immune checkpoint blockade. An underappreciated but significant contributor to immune suppression in tumors is the expression of the membrane phospholipid phosphatidylserine (PS) on the surface of tumor cells and tumor-derived microvesicles. PS is recognized by receptors on immune cells where it triggers the secretion of immune suppressive cytokines, prevents the differentiation of myeloid-derived suppressor cells (MDSCs) and inhibits dendritic cell (DC) maturation; events that prevent a productive anti-tumor T cell response. Bavituximab, a chimeric monoclonal antibody that targets PS and inhibits PS-mediated immunosuppressive signaling, drives immune activation by reducing the levels of MDSCs, by polarizing tumor-associated macrophages towards an M1 phenotype and by promoting the maturation of dendritic cells (DCs).
METHODS: The efficacy of bavituximab, anti-PD-1 and combination therapy was evaluated in multiple syngeneic, pre-clinical tumor models. Treatment efficacy was determined by inhibition of tumor growth and by immunophenotyping of spleen and tumor infiltrating leukocytes.
RESULTS: The combination of antibody-mediated PS and PD-1 blockade was significantly more effective in reducing tumor burden and promoting immune activation than single agent therapy. Combination therapy increased tumor infiltration of effector T-cells (Teff), increased the Teff:T regulatory cell ratio in the tumor and enhanced Teff function as determined by IFN-y, TNFa and granzyme B levels associated with Teff cells in the spleen and tumor. Furthermore combined blockade of PS and PD-1 signaling reduced the level of immune suppressive cells (e.g., MDSCs, M2 macrophages, and Treg) in the tumor microenvironment.
CONCLUSION: These results raise the possibility that PS blockade with bavituximab can enhance the efficacy of anti-PD-1 therapy even in patients with tumors that are unresponsive to single agent immune checkpoint therapy.
= = = = =
• RECALL: PPHM KOL/SAB Dr. David Carbone becomes President of IASLC 9-9-15 ( https://www.iaslc.org/about-us/board ). “…I also personally find it rewarding to participate in the global fight against cancer, and am honored to have been elected President of the IASLC, eff. Sept. 9, 2015." http://www.supportohiostate.org/site/TR?px=1009121&fr_id=1151&pg=personal
• IASLC Faculty & Staff Disclosures: Heather A. Wakelee, MD - Grant/Research Support: Genentech/Roche, Lilly, Pfizer, Novartis, Exelixis, Xcovery, AstraZeneca, Clovis, Regeneron; Consultant: Peregrine. http://www.gotoper.com/conferences/ilc/meetings/15th-international-lung-cancer-congress “Associate Prof. of Medicine, Div. of Oncology; Faculty Director, Cancer Clinical Trials Office; Co-leader, Lung Cancer Disease Mgt Group, Stanford Univ. School of Medicine, Stanford CA”
= = = = = = =
BAVI MOA 8-26-15: Jeff Hutchins(VP/PreClin-Res) ImVacS’15 Talk – 29pg. Slideshow http://tinyurl.com/qz64pzg
…“Expansion & Activation of T Cells via the Targeting of the Immunosuppressive Ligand PS: Combination Strategy with Conventional, Targeted, and Checkpoint Inhibitor Therapy”
5-31-15: ASCO’15 Roundtable (webcast), “Raising the Immuno-Oncology Bar” - 7 panel members, incl. 3 Sloan Kettering researchers http://tinyurl.com/qxu4w2x
BAVI MOA 3-25-15: PPHM/VP Dr. Jeff Hutchins’ presentation at "Immune Checkpoint Inhibitors Conf.", Boston - PDF(34 Slides): http://tinyurl.com/ooxkhq7
BAVI MOA 2-9-15: PPHM/VP Dr. Bruce Freimark’s presentation at KEYSTONE "Tumor Immunology Meeting", Banff/CN – PR & Slides: http://tinyurl.com/q6cx4w6
BAVI MOA 12-12-14 San Antomio Breast Cancer Symposium, Dr. Bruce Freimark, Bavi+anti-PD-1 vs. Breast Cancer http://tinyurl.com/p5ng6vs
BAVI MOA 11-2014 SITC’14: 3 posters on preclin. Bavi+aCTLA4/aPD1 combo data (Hutchins Freimark Brekken Huang etal) http://tinyurl.com/pchzr6h
BAVI MOA 8-28-14: Italy’s Dr. Federico Cappuzzo, Bavi/NSCLC profile article (DovePress OpenAccess, 7pgs) - http://tinyurl.com/n3oa7bc
BAVI MOA 8-11-14: PPHM/VP Dr. Jeff Hutchins’ presentation at ImVacS "Immunotherapies & Vaccine Summit", Boston - PR: http://tinyurl.com/lpjy3u7 ; PDF(31 Slides): http://tinyurl.com/oueldme
...MLV’s Dr. George Zavoico’s 8-27-14 report on Dr. Jeff Hutchins’ 8-11-14 ImVacS/Boston Bavi MOA presentation: http://tinyurl.com/l3tw63c
BAVI MOA 5-28-14: Dr. Rolf Brekken’s 47min CRI “Cancer Immunotherapy” webinar about Bavituximab as an Upstream/Global Immune Checkpoint Inhibitor – REPLAY: http://tinyurl.com/lxgftyx
. . .CRI=Cancer Research Institute (NYC – Supported by BMS): http://www.cancerresearch.org - Facebook: http://tinyurl.com/pbmhb2z , https://twitter.com/CancerResearch
. . .CRI launches “Answer to Cancer” (cancer immunotherapy) website http://www.theanswertocancer.org
. . .8-12-14: CRI adds Youtube links to the 5-28-14 CRI Immunotherapy webinar, incl. Dr. Brekken's talk "about Bavi and how it works against lung, liver, and other kinds of cancers" http://tinyurl.com/ps5h6h8
BAVI MOA 3-25-14: Dr. Rolf Brekken’s 40min talk at NYAS Lung Cancer Symposium http://tinyurl.com/lq9stnk (45 Slides)
. . .Dr.Brekken’s talk: “Antibody-mediated Inhibition of PS - A Novel Strategy for Immune Checkpoint Blockade” (the 5 speakers: Jessica Donington, Roy Herbst, Balazs Halmos, Suresh Ramalingam, Rolf Brekken)
12-10-13: With recent scientific insights highlighting bavi’s immunostimulatory moa, these additions to PPHM’s SAB: Dimitry Gabrilovich, Scott Antonia, David Carbone**, Hakan Mellstedt http://tinyurl.com/mw776mk
......**A/o 9-2014, Dr. David Carbone (PPHM SAB/KOL) is President-Elect of IASLC https://www.iaslc.org/about-us/board
BAVI MOA: 12-2013 Bavi’s Immunotherapeutic MOA overviewed by UTSW’s Brekken/Huang in Pan European Networks Jrnl. http://tinyurl.com/lnb46pq
(recall, UTSW’s Dr. Rolf Brekken gives an Oral Pres. tomorrow, Sept9, discussing, “previously announced study findings demonstrating that a combination of bavituximab and an anti-PD-1 antibody was more effective at reducing tumor burden in preclinical lung cancer models than either treatment alone.”)
Sept6-9 2015: “IASLC’s 16th World Conf. on Lung Cancer”, Denver
http://wclc2015.iaslc.org/
“The World Conference on Lung Cancer (WCLC) is the world’s largest meeting dedicated to lung cancer and other thoracic malignancies. More than 7,000 delegates come from more than 100 countries to discuss the latest developments in thoracic malignancy research. Attendees include surgeons, medical oncologists, radiation oncologists, pulmonologists, radiologists, pathologists, epidemiologists, basic research scientists, nurses, allied health professionals, advocates, and patients.”
http://www.iaslc.org/events/16th-world-conference-lung-cancer
2015 Exhibitor: Peregrine Pharm. (1 of 39) - booth #1724 (adjacent to Abbvie)
- - - - - - - - - - - - - - - - - - - - - - -
WCLC 2015 Track: Treatment of Advanced Diseases - NSCLC
9/7/15 9:30am-5:00pm, Exhibit Hall (Hall B+C)
POSTER #P1.01-075: “Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)
David R. Spigel, Joseph Shan, Alberto Chiappori, Ulrich Keilholz, Martin Reck, Martin Edelman, Manuel Domine, Keunchil Park, Tae Won Jang, Wu-Chou Su, Rachel E. Sanborn, Leora Horn, Rebecca Heist, Paul Mainwaring, David E. Gerber (UTSW)
ABSTRACT…
BACKGROUND: Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-B and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-a and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous NSCLC, bavituximab 3 mg/kg + docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 mos) in median overall survival (OS) compared to control.
METHODS: SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in Dec.2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and 2 interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every 2 cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.
RESULTS: Trial in progress
CONCLUSION: Trial in progress
POSTER: http://www.peregrineinc.com/images/stories/pdfs/iaslc_2015_sunrise.pdf
From Peregrine’s 9-8-15 PR:
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=930479
"A large and growing body of research continues to support our belief that, as a fundamental checkpoint inhibitor, bavituximab may have the potential to broadly enhance the therapeutic activity of a range of cancer treatments including chemotherapy, radiation and immunotherapies. These latest data being presented at the World Conference on Lung Cancer specifically highlight this synergistic potential in the area of checkpoint inhibitors by clearly illustrating the manner in which bavituximab is able to induce the appropriate immune responses required for a successful therapeutic response to anti-PD-1 & anti-PD-L1 agents," said Steven W. King, President and CEO of Peregrine. "We look forward to continuing our investigation of bavituximab in combination with other immuno-oncology agents through our ongoing collaborations with AstraZeneca, the Memorial Sloan Kettering Cancer Center and UT Southwestern."
- - - - - - - - - - - - - - - - - - - - - - -
WCLC 2015 Track: MINI ORAL #14 - Pre-Clinical Therapy (ID 119)
Moderators: Lynnette Fernandez-Cuesta Adi F. Gazdar
9/8/15, 10:45am-12:15pm, Mile High Ballroom 2c-3c
MINI-ORAL #14.07: “Bavituximab Activates CD8+ TILs in a 3D Ex Vivo System of Lung Cancer Patients Derived Tumors With Negative PD-L1 Expression”
Soner Altiok, Melanie Mediavilla Valera, Jenny Kreahling, Nikoletta L. Kallinteris, David Noyes, Tiffany N. Razabdouski, Joseph Shan, Jeff Hutchins, Kerstin Menander, Scott J. Antonia (Moffitt CC)
ABSTRACT…
BACKGROUND: Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Bavituximab blocks PS-mediated immune suppression and activates cytotoxic T lymphocyte anti-tumor responses.
METHODS: Tissues from consented patients with adenocarcinoma of the lung were extracted at the time of surgical resection and disaggregated to characterize expression of immune checkpoint proteins such as PD-1, CTLA-4, LAG3, TIM3, BTLA and adenosine A2A receptor on both CD4+ and CD8+ tumor infiltrating cells by flow cytometry (FACS) and stained for PD-L1, CD68, and CD163 via immunohistochemistry (IHC). 3D tumor microspheres were prepared and treated ex vivo with an IgG control, F(ab)’2 version of bavituximab, bavituximab, docetaxel, anti-PD-1 or PD-L1 and combinations of bavituximab, anti-PD-1 or PD-L1 and docetaxel for 36 hours within an intact tumor microenvironment. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by treatment. In a few cases, the expanded TILs were tested in PDX models using the consented patient’s tumor.
RESULTS: Bavituximab induces activation of TILs in 3D ex vivo tumor microsphere models of lung cancer, as demonstrated by a significant increase in IFN-y, TNF-a, and GM-CSF secretion. FACS, IHC, and NanoString gene function analysis read out assays revealed that this effect was associated with low PD-1 expression on CD8+ cells, negative PD-L1 expression in the stating biopsy tissue, and a conversion of the M2 to M1 macrophage phenotype.
CONCLUSION: These data support the use of bavituximab as an immunomodulatory treatment in adenocarcinoma of the lung by enhancing the activation of CD8+ TIL derived from patients' tumors with negative PD-L1 expression; correlating with increased cytokine production by lymphoid cells and repolarization of myeloid cells from an immunosuppressive to an immune active state.
SLIDESHOW (9 pgs.): http://www.peregrineinc.com/images/stories/pdfs/iaslc_2015_altiok.pdf
From Peregrine’s 9-8-15 PR:
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=930479
”For the study presented at the WCLC, researchers from Nilogen Oncosystems [<=Moffitt Startup: http://otmc.moffitt.org/startups.aspx ] and the H. Lee Moffitt Cancer Center, in collaboration with Peregrine, evaluated immune changes in 3D tumor microspheres generated from human NSCLC fresh tumors extracted at the time of surgery. These were tumor microspheres were treated with bavituximab alone, docetaxel alone, a combination of bavituximab and docetaxel, and a control. Bavituximab, alone and in combination with docetaxel, induced activation of tumor infiltrating lymphocytes as demonstrated by a statistically significant increase in key immune-stimulating cytokines such as IFN-y, TNF-a, and GM-CSF with a corresponding decrease in secretion of the immunosuppressive cytokine IL-10. Importantly, the bavituximab-affected immune response activity appeared to correlate with low PD-L1 expression on the tumor samples. "These new translational data suggest that bavituximab has the potential to activate a tumor specific immune response in patients with PD-L1 negative tumors that generally do not respond as well to immune checkpoint inhibitors. By doing so, it is believed that bavituximab may hold potential to increase the number of patients able to respond to PD-1 & PD-L1 targeting immunotherapies," said Jeff Hutchins, VP, Preclinical Dev. of Peregrine. "These findings continue to expand our collection of translational data supporting the mechanism of action for bavituximab and corroborate our wide range of previously published preclinical study results. Taken together, these data provide us with growing confidence for our bavituximab development programs, including the ongoing Phase III SUNRISE clinical trial in NSCLC which is evaluating the same treatment combination used in these studies."
- - - - - - - - - - - - - - - - - - - - - - -
WCLC 2015 Track: ORAL #41 - Immune Biology, Microenvironment & Novel Targets (ID 159)
Moderators: Sukhmani K. Padda, Raphael Nemenoff
9/9/15, 6:30-8:00pm, Four Seasons Ballroom F1+F2
ORAL #41.05: “Targeting Phosphatidylserine-Mediated Immune Suppression Enhances the Efficacy of Immune Checkpoint Blockade in Pre-Clinical Tumor Models”
Rolf A. Brekken (UTSW), Bruce Freimark, Jian Gong, Carrie Baldwin, Van Nguyen, Michael Gray, Shen Yin, Jeff Hutchins, Alan Schroit, Xianming Huang (UTSW)
ABSTRACT…
BACKGROUND: Despite substantial progress, only a subset of cancer patients benefit from blockade of the PD-1 immune checkpoint. Multifocal immune suppression in the tumor microenvironment is the underlying cause for the limited efficacy of immune checkpoint blockade. Persistent immune suppression prevents the development of a robust T cell response to tumor specific antigens that is required for effective downstream immune checkpoint blockade. An underappreciated but significant contributor to immune suppression in tumors is the expression of the membrane phospholipid phosphatidylserine (PS) on the surface of tumor cells and tumor-derived microvesicles. PS is recognized by receptors on immune cells where it triggers the secretion of immune suppressive cytokines, prevents the differentiation of myeloid-derived suppressor cells (MDSCs) and inhibits dendritic cell (DC) maturation; events that prevent a productive anti-tumor T cell response. Bavituximab, a chimeric monoclonal antibody that targets PS and inhibits PS-mediated immunosuppressive signaling, drives immune activation by reducing the levels of MDSCs, by polarizing tumor-associated macrophages towards an M1 phenotype and by promoting the maturation of dendritic cells (DCs).
METHODS: The efficacy of bavituximab, anti-PD-1 and combination therapy was evaluated in multiple syngeneic, pre-clinical tumor models. Treatment efficacy was determined by inhibition of tumor growth and by immunophenotyping of spleen and tumor infiltrating leukocytes.
RESULTS: The combination of antibody-mediated PS and PD-1 blockade was significantly more effective in reducing tumor burden and promoting immune activation than single agent therapy. Combination therapy increased tumor infiltration of effector T-cells (Teff), increased the Teff:T regulatory cell ratio in the tumor and enhanced Teff function as determined by IFN-y, TNFa and granzyme B levels associated with Teff cells in the spleen and tumor. Furthermore combined blockade of PS and PD-1 signaling reduced the level of immune suppressive cells (e.g., MDSCs, M2 macrophages, and Treg) in the tumor microenvironment.
CONCLUSION: These results raise the possibility that PS blockade with bavituximab can enhance the efficacy of anti-PD-1 therapy even in patients with tumors that are unresponsive to single agent immune checkpoint therapy.
= = = = =
• RECALL: PPHM KOL/SAB Dr. David Carbone becomes President of IASLC 9-9-15 ( https://www.iaslc.org/about-us/board ). “…I also personally find it rewarding to participate in the global fight against cancer, and am honored to have been elected President of the IASLC, eff. Sept. 9, 2015." http://www.supportohiostate.org/site/TR?px=1009121&fr_id=1151&pg=personal
• IASLC Faculty & Staff Disclosures: Heather A. Wakelee, MD - Grant/Research Support: Genentech/Roche, Lilly, Pfizer, Novartis, Exelixis, Xcovery, AstraZeneca, Clovis, Regeneron; Consultant: Peregrine. http://www.gotoper.com/conferences/ilc/meetings/15th-international-lung-cancer-congress “Associate Prof. of Medicine, Div. of Oncology; Faculty Director, Cancer Clinical Trials Office; Co-leader, Lung Cancer Disease Mgt Group, Stanford Univ. School of Medicine, Stanford CA”
= = = = = = =
BAVI MOA 8-26-15: Jeff Hutchins(VP/PreClin-Res) ImVacS’15 Talk – 29pg. Slideshow http://tinyurl.com/qz64pzg
…“Expansion & Activation of T Cells via the Targeting of the Immunosuppressive Ligand PS: Combination Strategy with Conventional, Targeted, and Checkpoint Inhibitor Therapy”
5-31-15: ASCO’15 Roundtable (webcast), “Raising the Immuno-Oncology Bar” - 7 panel members, incl. 3 Sloan Kettering researchers http://tinyurl.com/qxu4w2x
BAVI MOA 3-25-15: PPHM/VP Dr. Jeff Hutchins’ presentation at "Immune Checkpoint Inhibitors Conf.", Boston - PDF(34 Slides): http://tinyurl.com/ooxkhq7
BAVI MOA 2-9-15: PPHM/VP Dr. Bruce Freimark’s presentation at KEYSTONE "Tumor Immunology Meeting", Banff/CN – PR & Slides: http://tinyurl.com/q6cx4w6
BAVI MOA 12-12-14 San Antomio Breast Cancer Symposium, Dr. Bruce Freimark, Bavi+anti-PD-1 vs. Breast Cancer http://tinyurl.com/p5ng6vs
BAVI MOA 11-2014 SITC’14: 3 posters on preclin. Bavi+aCTLA4/aPD1 combo data (Hutchins Freimark Brekken Huang etal) http://tinyurl.com/pchzr6h
BAVI MOA 8-28-14: Italy’s Dr. Federico Cappuzzo, Bavi/NSCLC profile article (DovePress OpenAccess, 7pgs) - http://tinyurl.com/n3oa7bc
BAVI MOA 8-11-14: PPHM/VP Dr. Jeff Hutchins’ presentation at ImVacS "Immunotherapies & Vaccine Summit", Boston - PR: http://tinyurl.com/lpjy3u7 ; PDF(31 Slides): http://tinyurl.com/oueldme
...MLV’s Dr. George Zavoico’s 8-27-14 report on Dr. Jeff Hutchins’ 8-11-14 ImVacS/Boston Bavi MOA presentation: http://tinyurl.com/l3tw63c
BAVI MOA 5-28-14: Dr. Rolf Brekken’s 47min CRI “Cancer Immunotherapy” webinar about Bavituximab as an Upstream/Global Immune Checkpoint Inhibitor – REPLAY: http://tinyurl.com/lxgftyx
. . .CRI=Cancer Research Institute (NYC – Supported by BMS): http://www.cancerresearch.org - Facebook: http://tinyurl.com/pbmhb2z , https://twitter.com/CancerResearch
. . .CRI launches “Answer to Cancer” (cancer immunotherapy) website http://www.theanswertocancer.org
. . .8-12-14: CRI adds Youtube links to the 5-28-14 CRI Immunotherapy webinar, incl. Dr. Brekken's talk "about Bavi and how it works against lung, liver, and other kinds of cancers" http://tinyurl.com/ps5h6h8
BAVI MOA 3-25-14: Dr. Rolf Brekken’s 40min talk at NYAS Lung Cancer Symposium http://tinyurl.com/lq9stnk (45 Slides)
. . .Dr.Brekken’s talk: “Antibody-mediated Inhibition of PS - A Novel Strategy for Immune Checkpoint Blockade” (the 5 speakers: Jessica Donington, Roy Herbst, Balazs Halmos, Suresh Ramalingam, Rolf Brekken)
12-10-13: With recent scientific insights highlighting bavi’s immunostimulatory moa, these additions to PPHM’s SAB: Dimitry Gabrilovich, Scott Antonia, David Carbone**, Hakan Mellstedt http://tinyurl.com/mw776mk
......**A/o 9-2014, Dr. David Carbone (PPHM SAB/KOL) is President-Elect of IASLC https://www.iaslc.org/about-us/board
BAVI MOA: 12-2013 Bavi’s Immunotherapeutic MOA overviewed by UTSW’s Brekken/Huang in Pan European Networks Jrnl. http://tinyurl.com/lnb46pq
