Tuesday, November 15, 2016 1:56:54 PM
11-14-16/PR: SITC’16, PPHM+MSKCC PS-Targeting Data Presented. Dr.Jedd.Wolchok states, “Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model. It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact."...
11-11-16:
11-11-16:
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]
11-14-16/PR: Dr. Jedd Wolchok: "Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model. It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact."
11-14-16/PR: Dr. Taha Merghoub (Co-Dir., Ludwig Collaborative Lab at MSK): "We have noted that the combination of PS-targeting treatment and radiation, as well as triple combination of PS-targeting treatment, radiation and anti-PD-1, resulted in clear advantages in anti-tumor activity in the mouse B16 melanoma model. We believe that these findings suggest the potential benefit of combining these agents to improve the outcomes of patients with cancer. With this in mind, we think this research may play an important role in designing future clinical trials of PS-targeting agents in melanoma and other cancers."
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11-14-16/PR: New Study Demonstrates Anti-Tumor Advantages for Combination Treatment Featuring Peregrine Pharmaceuticals' PS-Targeting Antibodies in a Preclinical Melanoma Model
* Promising Results of MSK Study Evaluating Combinations of PS-Targeting Treatment, Anti-PD-1 and Radiation in Mouse B16 Melanoma Model Presented at SITC 2016
* New Data from Second Study Conducted by Peregrine Shows Triple Combination of PS-Targeting Treatment, Anti-PD-1 and Anti-LAG3 Created Long-Term Immunity in Triple Negative Breast Cancer Model; Protected Animals when Re-Challenged with Breast Cancer Cells
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=999202
TUSTIN, Nov. 14, 2016: Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM/PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, today announced the presentation of positive data from multiple new preclinical studies of the company's phosphatidylserine (PS)-targeting antibodies. Study results highlight that PS-targeting antibodies similar to bavituximab synergize with checkpoint inhibitors and radiation to improve anti-tumor activity in various animal tumor models. Importantly, the improved anti-tumor activity seen in these studies was even greater when PS-targeting therapy was a part of triple combination treatment including anti-PD-1 and another therapy. Data were presented by Peregrine scientists, as well as researchers from Memorial Sloan Kettering Cancer Center (MSK), at the Society for Immunotherapy of Cancer (SITC) 2016 Annual Meeting, which was held November 9-13, 2016 in National Harbor, MD. [ http://www.sitcancer.org/2016 ]
Initial results from Peregrine's ongoing collaboration with MSK researchers were featured in a poster presented by Sadna Budhu, PhD, at SITC 2016. A team of MSK researchers led by cancer immunotherapy thought-leaders, Taha Merghoub, PhD and Jedd D. Wolchok, MD, PhD [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ], evaluated the effects of combining PS-targeting, anti-PD-1 and radiation therapies in the mouse B16 melanoma model. Study data showed that PS-targeting antibodies synergize with both anti-PD-1 and radiation therapy to improve anti-cancer activity. PS-targeting treatment in combination with radiation, as well as triple combination of PS-targeting treatment, anti-PD-1 and radiation, led to a reduction in tumor burden. Median survival for the triple combination treatment still had not been reached at the end of the 80-day observation period with other arms in the study showing median survival that ranged from 24-70 days.
Researchers also evaluated the impact of the PS-targeting and radiation combination treatment on the level and type of immune activity. These results demonstrated that the combination led to a change in the tumor microenvironment, shifting it from immunosuppressive in which tumors are protected to immune active in which tumors are more susceptible to treatment. Analysis of local immune responses in the tumors of the treated animals showed that the combination treatment increased the number of tumor associated macrophages and shifted the macrophage polarization from the immunosuppressive M2 type to the immune active M1 type. When systemic immune responses were analyzed following triple combination of PS-targeting treatment, anti-PD-1 and radiation, researchers also saw evidence of increased immune activity. This was illustrated by key indicators of immune activity, including increases in CD8+ T-cell activation, effector cytokine production and differentiation into effector memory cells.
"Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model," stated Dr. Jedd Wolchok. "It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact."
"We have noted that the combination of PS-targeting treatment and radiation, as well as triple combination of PS-targeting treatment, radiation and anti-PD-1, resulted in clear advantages in anti-tumor activity in the mouse B16 melanoma model," said Dr. Taha Merghoub, PhD, co-director of the Ludwig Collaborative Laboratory at MSK. "We believe that these findings suggest the potential benefit of combining these agents to improve the outcomes of patients with cancer. With this in mind, we think this research may play an important role in designing future clinical trials of PS-targeting agents in melanoma and other cancers."
[Note: FULL SITC’16 ABSTRACT #199: http://bit.ly/2dHTEVn
...Full Poster Image: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]
A second study, conducted by Peregrine, evaluated the effects of combining PS-targeting, anti-PD-1 and anti-LAG3 therapies in the E0771 triple negative breast cancer (TNBC) model. Initial findings from this study were previously reported and demonstrated that eight of the ten (80%) animals receiving the PS-targeting, anti-PD-1 and anti-LAG3 treatment combination experienced complete tumor regressions, whereas there were no animals (0/10) in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression. New data presented for the first time at SITC demonstrated that the triple combination established a specific and prolonged anti-tumor immune response which protected those eight animals that achieved a complete tumor regression against a re-challenge with the same E0771 TNBC model tumor cells. This sustained anti-tumor response demonstrates the ability of the triple combination treatment to trigger immune system memory and support adaptive immune responses against reemerging disease in the E0771 TNBC model.
[Note: FULL SITC’16 ABSTRACT #213: http://bit.ly/2dpUy4C ]
...Full Poster Image: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gray.pdf ]
Further highlighting the immune impact of the PS-targeting/anti-PD-1/anti-LAG3 treatment combination were initial results of a new analysis from this study using the nCounter ® PanCancer Immune Profiling Panel from NanoString Technologies ®. Data from the analysis demonstrated that the triple combination induced a greater shift in the tumor microenvironment from immunosuppressive to immune active as compared to all other treatment groups. This was evidenced by greater increases in the activity of several critical immune activating pathways, including presentation and processing of antigens and signaling and activation of T-cells, for the triple combination as compared to all other treatments.
"It is very encouraging to see the consistent increase in anti-tumor activity triggered by triple combination treatments that combine PS-targeting agents and anti-PD-1 with other cancer treatments. By demonstrating this activity across multiple studies in multiple tumor models, we are continuing to build scientific support for the therapeutic potential of adding PS-targeting therapies in combination with other cancer treatments, including checkpoint inhibitors such as anti-PD-1," said Jeff T. Hutchins, PhD, Peregrine's VP, Preclinical Research. "As cancer research continues to explore the potential of combination treatments that marry complementary mechanisms, we are pleased to see that our efforts continue to generate data supporting the role that PS-targeting agents such as bavituximab may play in this area."
Bavituximab is an investigational monoclonal antibody that targets PS. Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. Previous studies demonstrated PS-targeting antibodies shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor responses. Peregrine continues to support and guide clinical development through the evaluation of the preclinical equivalent of bavituximab, ch1N11, in animal model studies.
Peregrine's clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants awarded by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations [See: http://tinyurl.com/gutgwb5 ]. These trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination. Additionally, Peregrine continues to advance its pre-clinical collaboration with Memorial Sloan Kettering Cancer Center with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab's combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.
ABOUT PEREGRINE PHARMACEUTICALS, INC.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company committed to improving the lives of patients by delivering high quality pharmaceutical products through its contract development and manufacturing organization (CDMO) services and through advancing and licensing its investigational immunotherapy and related products. Peregrine's in-house CDMO services, including cGMP manufacturing and development capabilities, are provided 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. The company is also working to evaluate its lead immunotherapy candidate, bavituximab, in combination with immune stimulating therapies for the treatment of various cancers, and developing its proprietary exosome technology for the detection and monitoring of cancer. For more information, please visit http://www.peregrineinc.com .
Safe Harbor *snip*
Contacts:
Stephanie Diaz (Investors), Vida Strategic Partners, 415-675-7401, sdiaz@vidasp.com
Tim Brons (Media), Vida Strategic Partners, 415-675-7402, tbrons@vidasp.com
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iHub Poster FireFOX’s Commentary on the Joint MSKCC/PPHM SITC’16 News
11-15-16: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=126566507
SUBJ: IMPORTANCE OF WOLCHOK’S REMARKS IN YESTERDAY’S PR.
The key to partnerships comes from Wolchok’s confirmation that Bavi “creates a more immune active environment in which other treatments are able to have greater anti-tumor impact.”
Look how this remark echoes and reinforces comments by Dr. Perlmutter, head of IO research at Merck, in an October ESMO article on Keytruda vs. Opdivo. Dr. Perlmutter explained that higher levels of PD-L1 confer a greater benefit from PD-1 blockers and, “It turns out PD-L1 expression is just a marker for the presence of an immune response.” Here is a quote from the article:
“So what does PD-L1 expression mean — and why do higher levels confer a greater benefit from PD-1 blockers?
"It turns out PD-L1 expression is just a marker for the presence of an immune response," explained Merck's head of research, Dr. Roger Perlmutter. "Expression of PD-L1 is increased by immune response factors."
IN ENGLISH: PD-L1 is a signal that the immune system has been trying to fight the cancer. Or, as Perlmutter puts it, "Gee, there's already an immune response going on here."
http://www.cnbc.com/2016/10/07/bristol-myers-mercks-lung-cancer-treatments-square-off-this-weekend.html
This is why Wolchok’s comment yesterday is so important when he confirmed that Bavi’s MOA is to “create a more immune active environment”:
DR. JEDD WOLCHOK STATES (11-14-16), “Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model. It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact.
The really important part of the MSK poster, the part that will wake up all the BP decision makers, is not the mice survival data, but rather all the detailed work MSK did to confirm that Bavi is indeed triggering an upstream immune response, e.g. increase in CD8 T-cells, shift of macrophage from M2 to M1. MSK summarizes this “creation of a more active immune environment” in the 3rd & 4th bullet points of the Poster Conclusion. This is just what Dr. Perlmutter at Merck said was missing in the 80% of patients that don’t respond to PD-1. To quote Perlmutter, Keytruda & Opdivo work better when the clinician can say "Gee, there's already an immune response going on here."
There is now strong evidence from the MSK poster and Wolchok’s summary comments that Bavi triggers an upstream immune response. This will be a huge boost to the ongoing partnership talks. *end*
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MSKCC/Wolchok-Lab & PPHM, Nov11-12, Natl-HarborMD. 3 PS-Targeting/I-O Abstracts – note that the 1st one (#199 Nov. 11, 2016) is the joint MSKCC/PPHM one; its Senior author is Dr. Taha Merghoub (Jedd Wolchok Lab, Memorial Sloan Kettering), who said this in the 5-29-15 PPHM/MSK Collab. Announcement PR (see below): "A key focus of the Wolchok Lab's research is studying novel immunotherapy combinations that work together to enable the immune system to recognize & destroy cancer. This collaboration will allow us to focus on the role & contribution of PS blockade therapy in determining which combination of the current and next generation of immune modulators is likely to increase the extent and amplitude of anti-tumor response. This important pre-clinical & translational work will potentially guide the design of the next generation of clinical studies with bavituximab."
Nov9-13 2016: “(SITC) Society for Immunotherapy of Cancer 31st Annual Meeting”, Natl-Harbor MD
”The premier destination for scientific exchange, education, and networking in the Cancer Immunotherapy Field”
SITC = The Society for Immunotherapy of Cancer http://www.sitcancer.org
SITC 2016 Meeting: http://www.sitcancer.org/2016
Abstracts: http://www.sitcancer.org/2016/abstracts
PEREGRINE/MSKCC ABSTRACTS:
I. 11-11-16 12:15-1:30pm #199: “Phosphatidylserine Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma” - Sadna Budhu, PhD - Ludwig Collaborative Lab, MSKCC (Memorial Sloan Kettering)
AUTHORS: Sadna Budhu(MSKCC PRESENTING AUTHOR) 1, Olivier De Henau 2, Roberta Zappasodi 1, Kyle Schlunegger 3, Bruce Freimark 4, Jeff Hutchins 5, Christopher A. Barker 6, Jedd D. Wolchok 7, Taha Merghoub(MSKCC SENIOR AUTHOR) 1 [<=See 5-29-15 PPHM/MSKCC PR below]
1/2 Ludwig Collaborative Lab, Memorial Sloan Kettering CC, NYC
6 Memorial Sloan Kettering CC, NYC
7 Dept of Medicine, Memorial Sloan Kettering CC, NYC
3/4/5 Peregrine Pharmaceuticals, Tustin, CA
ABSTRACT: http://bit.ly/2dHTEVn POSTER PDF: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf
II. 11-12-16 11:45-1pm #210: “Antibody Targeting of Phosphatidylserine Enhances the Anti-Tumor Responses of Ibrutinib & anti-PD-1 Therapy in a Mouse Triple Negative Breast Tumor Model” - Jian Gong, PhD - Peregrine Pharmaceuticals
AUTHORS: Jian Gong, Michael Gray, Jeff Hutchins, Bruce Freimark - Peregrine Pharm. ABSTRACT: http://bit.ly/2dpUh1w POSTER PDF: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gong.pdf
III. 11-11-16 12:15-1:30pm #213: ”Monoclonal Antibodies Targeting Phosphatidylserine Enhance Combinational Activity of the Immune Checkpoint Targeting Agents LAG3 & PD-1 in Murine Breast Tumors” - Michael Gray, PhD - Peregrine Pharmaceuticals
AUTHORS: Michael Gray, Jian Gong, Jeff Hutchins, Bruce Freimark - Peregrine Pharm. ABSTRACT: http://bit.ly/2dpUy4C POSTER PDF: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gray.pdf
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http://resource-cms.springer.com/springer-cms/rest/v1/content/11027680/data/v1/Volume+4+Supplement+1+PDF+pt+2
I . #199/SITC’16/11-11-16(MSK+PPHM): “Phosphatidylserine Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma”
AUTHORS:
Sadna Budhu(MSKCC PRESENTING AUTHOR) 1, Olivier De Henau 2, Roberta Zappasodi 1, Kyle Schlunegger 3, Bruce Freimark 4, Jeff Hutchins 5, Christopher A. Barker 6, Jedd D. Wolchok 7, Taha Merghoub(Memorial Sloan Kettering SENIOR AUTHOR)
BACKGROUND:
Phosphatidylserine (PS) is a phospholipid that is exposed on the surface of apoptotic cells, some tumor cells and tumor endothelium. PS has been shown to promote anti-inflammatory and immunosuppressive signals in the tumor microenvironment. Antibodies that target PS have been shown to reactivate anti-tumor immunity by repolarizing tumor associated macrophages to a M1-like phenotype, reducing the number of MDSCs in tumors and promote the maturation of dendritic cells into functional APCs. In a B16 melanoma model, targeting PS in combination with immune checkpoint blockade has been shown to have a significantly greater anti-cancer effect than either agent alone. This combination was shown to enhance CD4+ and CD8+ T cell infiltration and activation in the tumors of treated animals. Radiation therapy is an effective focal treatment of primary solid tumors, but is less effective in treating metastatic solid tumors as a monotherapy. There is evidence that radiation induces immunogenic tumor cell death and enhances tumor-specific T cell infiltration in irradiated tumors. In addition, the abscopal effect, a phenomenon in which tumor regression occurs outside the site of radiation therapy, has been observed in both preclinical and clinical trials with the combination of radiation therapy and immunotherapy.
METHODS:
We examined the effects of combining tumor radiation therapy with an antibody that targets PS (1 N11) [Note: PGN635 (B2GPI-dep.) is Fully-Human Bavituximab=1N11=AT004; Genentech studying 89Zr-PGN635 as a Tumor Imaging Agent, “indep. of cancer type”] and an immune checkpoint blockade (anti-PD-1) using the mouse B16 melanoma model. Tumor surface area and overall survival of mice were used to determine efficacy of the combinations.
RESULTS:
We examined the expression of PS on immune cells infiltrating B16 melanomas. CD11b + myeloid cells expressed the highest levels of PS on their surface whereas T cells and B16 tumor cells express little to no PS. These data suggest that targeting PS in B16 melanoma would induce a pro-inflammatory myeloid tumor microenvironment. We hypothesize that therapies that induce apoptotic cell death on tumor cells would enhance the activity of PS-targeting antibodies. We therefore examined the effects of combining a PS-targeting antibody with local tumor radiation. We found that the PS-targeting antibody synergizes with both anti-PD-1 and radiation therapy to improve anti-cancer activity and overall survival. In addition, the triple combination of the PS-targeting antibody, tumor radiation and anti-PD-1 treatment displayed even greater anti-cancer and survival benefit.
CONCLUSIONS:
This finding highlights the potential of combining these 3 agents to improve outcome in patients with advanced-stage melanoma and may inform the design of future clinical trials with PS targeting in melanoma and other cancers *end*
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]
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II. #210/SITC’16/11-12-16(PPHM): “Antibody Targeting of Phosphatidylserine Enhances the Anti-Tumor Responses of Ibrutinib & anti-PD-1 Therapy in a Mouse Triple Negative Breast Tumor Model”
AUTHORS: Jian Gong, Michael Gray, Jeff Hutchins, Bruce Freimark - Peregrine Pharm.
BACKGROUND:
Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on vascular endothelial cells and tumor cells in the tumor microenvironment, particularly in response to chemotherapy and irradiation. Binding of antibodies targeting PS induces the recruitment of immune cells and engages the immune system to destroy tumor and associated vasculature and by blocking the immunosuppressive action of PS. Recent studies have demonstrated that PS-targeting antibodies enhance the anti-tumor activity of immune checkpoint antibody blockade to CTLA-4 and PD-1 in mouse breast and melanoma tumor models. Ibrutinib [Ibrutinib=Imbruvica, dev. by Pharmacyclics & J&J, acquired by ABBVIE in 2015, proj. global sales of $1B/2016, $5B/2020] is an approved anticancer drug targeting B cell malignancies that is a selective, covalent inhibitor Bruton's tyrosine kinase (BTK) in B cell tumors. Data from recent mouse tumor studies demonstrate that ibrutinib in combination with anti-PD-1 antibody blockade inhibits growth of solid tumors, lacking BTK expression, suggesting that ibrutinib may inhibit interleukin-2 inducible T cell kinase (ITK) and promote Th1 anti-tumor responses.
METHODS:
The present study was conducted to evaluate a combination therapy including PS-targeting antibody mch1N11, ibrutinib and anti-PD-1 antibody in C57Bl/6 mice bearing triple negative E0771 breast tumors. Tumors were staged to an initial volume of ~100 mm 3 and ran- domized to treatment groups (N=10) with mch1N11 or isotype control at 10 mg/kg qw, anti-PD-1 at 2.5 mg/kg qw or ibrutinib 6 mg/kg or vehicle qd x 8. Tumor volumes were measured twice per week to determine tumor growth inhibition (TGI) relative to control treated animals. The in vitro sensitivity of E0771 tumor cells to ibrutinib was compared to the drug sensitive Jeko-1 cell line in a 72 hour growth and viability assay.
RESULTS:
The E0771 cell line is resistant in vitro to 10 mM ibrutinib. Tumor bearing mice treated with mch1N11, ibrutinib or anti-PD-1 alone had 22.2 %, 23.5 % and 32.6 % TGI respectively. The TGI for mch1N11 and ibrutinib was 30.5 %, ibrutinib and anti-PD-1 was 34.5 %, mch1N11 and anti-PD-1 was 36.1 %. The triple combination therapy had statistically greater TGI compared to control treated mice (59.9 %, p = 0.0084).
CONCLUSIONS:
Treatment of solid tumors with a combination of inhibitors that target PS, ITK and the PD-1 D-L1 axis in the tumor microenvironment provides a novel treatment for solid tumors, including triple negative breast cancer. *end*
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gong.pdf ]
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III. #213/SITC’16/11-11-16(PPHM): ”Monoclonal Antibodies Targeting Phosphatidylserine Enhance Combinational Activity of the Immune Checkpoint Targeting Agents LAG3 & PD-1 in Murine Breast Tumors”
AUTHORS: Michael Gray, Jian Gong, Jeff Hutchins, Bruce Freimark - Peregrine Pharm.
BACKGROUND:
Our previous work demonstrated that the addition of phosphatidylserine (PS) targeting antibodies to anti-programmed death ligand 1 (PD-1) therapy in murine triple negative breast cancers (TNBC) significantly enhanced immune system activation and tumor growth inhibition. In these studies, NanoString immune profile analysis showed that intratumoral levels of lymphocyte activation ge ne 3 (LAG3) mRNA increased in response to PS and PD-1 treatments. This suggests LAG3 may act to attenuate T cell activation in TNBC du ring I/O therapeutic regimens; however, it is unknown if PD-1 and LAG3 function cooperatively in regulating T cell anergy, and whether adding PS blocking antibodies can further enhance the effectiveness of LAG3 and/or LAG3 + PD-1 therapies.
METHODS:
Animal studies utilized C57bl/6 mice implanted with the murine TNBC model E0771. Immunoprofiling analysis was performed by flow cytometry and the NanoString nCounter PanCancer Immune Profiling Panel. Antibody treatments utilized a specific phosphatidylserine targeting antibody (ch1N11), anti-PD-1, or anti-LAG3 alone or in combination. All statistical analysis utilized the student t-test (significant with p < 0.05). RESULTS: LAG3 and PD-1 were co-expressed on T cells in E0771. Mice treated with antibodies targeting PS, PD-1, and LAG3 alone in combination with each other demonstrated that the addition of PS blocking antibodies to anti-PD-1 therapy or LAG3 had significantly greater anti- tumor activity than either single agent. Comparison of PD-1 + LAG3 combinational therapy vs. single PD-1 or LAG3 treatments showed moderately more anti-tumor activity than single treatments; however, the addition of PS blocking antibodies to either checkpoint inhibitor was as equally effective in inhibiting tumor growth as observed in the combination of LAG3 + PD-1 treatment. Further comparison of PD-1 + LAG3 vs. PS + PD-1 + LAG3 treatments demonstrated that the addition of PS blocking antibodies resulted in a significant decrease in tumor growth accompanied by complete tumor regression in a greater number of animals than observed in the PD-1 + LAG3 treatment group. FACS and NanoString immunoprofiling analysis on each treatment group showed that the addition of PS blocking antibodies to all check- point treatment groups, including the combination of PD-1 + LAG3, resulted in enhanced tumor infiltrating lymphocytes (TILs), a reduction myeloid derived suppressor cells (MDSCs), and enhanced cytokines associated with immune system activation.
CONCLUSIONS Overall, our data demonstrate that while PS, LAG3, and PD-1 therapies each have efficacy in TNBC as single agents, I/O treatments that include PS blocking antibodies offer significantly improved growth inhibition and are capable of increasing TILs compared to single and combinational treatments by T cell checkpoint targeting inhibitors alone. *end*
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gray.pdf ]
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9-8-16/CC - JEFF HUTCHINS (VP/PreClinical Res.) http://tinyurl.com/jmy77g3
“...I would now like to provide an update on Peregrine's preclinical I-O focused internal efforts and our collaboration with Memorial Sloan Kettering Cancer Center. The goal of this work is to evaluate combinations of PS targeting with other checkpoint inhibitors and immune stimulatory agents for the purpose of developing new and increasingly effective anticancer treatments. These programs are advancing well and to-date, we have seen impressive signs of activity with new combinations of PS targeting and other treatment modalities such as checkpoint blockers, T-cell agonists and radiation. These new combinations are improving overall survival accompanied with increases in cyto-reactive T cells into the tumor tissue. This exciting new internal work will be presented at the AACR/CRI Immunotherapy Meeting in New York later this month [Sept25-28] and at ESMO in early October [Oct7-11: http://tinyurl.com/jxdppyo ]. We expect the first results from our collaboration with MSK’s Jedd Wolchok Lab investigators [See MSK Collab: http://tinyurl.com/zkvebh6 ] to be presented at SITC in November [Nov9-13: http://www.sitcancer.org/2016 Natl.Harbor MD] and we will provide more detailed information as that presentation becomes available.”
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5-29-15: Peregrine & Sloan Kettering Enter Collab. to “Investigate Novel PS-Targeting Immunotherapy Combos” http://tinyurl.com/o3k9ux8
...The studies at MSK will be performed under the direction of Taha Merghoub, PhD, [ http://www.mskcc.org/research-areas/labs/members/taha-merghoub-01 ] Associate Attending Biologist, Melanoma and Immunotherapeutics Service, Ludwig Collaborative and the Swim Across America Laboratory, a part of the laboratory of Jedd D. Wolchok, MD, PhD [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ], a leader in the field of cancer immunotherapy. Dr. Wolchok serves as the Chief, Melanoma and Immunotherapeutics Service, Lloyd J. Old Chair for Clinical Investigation as well as an Associate Director of the Ludwig Center for Cancer Immunotherapy at MSK.
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”The phosphatidylserine (PS) signaling pathway is a very interesting target for modulating the immune system's response to cancer. We look forward to exploring the potential of PS-targeting agents alone and with other immune modulators that may lead to novel advances in cancer therapy," said Dr. Jedd Wolchok.
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As part of the collaboration, researchers at MSK will conduct research to further explore the combination of PS-targeting agents, including bavituximab, that block a primary immunosuppressive pathway thereby allowing anti-tumor immune responses with other immuno-stimulatory agents that enhance immune responses. Specifically, MSK researchers will examine the combination of bavituximab alongside models of checkpoint blockade that are unresponsive to inhibition or co-stimulation given the ability of bavituximab to reprogram myeloid derived suppressor cells (MDSC) and increase tumoricidal T-cells in tumors, a mechanism of action that is complementary to checkpoint blockade and T-cell activation.
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"A key focus of the Wolchok Lab's research is studying novel immunotherapy combinations that work together to enable the immune system to recognize and destroy cancer. This collaboration will allow us to focus on the role and contribution of PS blockade therapy in determining which combination of the current and next generation of immune modulators is likely to increase the extent and amplitude of anti-tumor response. This important pre-clinical and translational work will potentially guide the design of the next generation of clinical studies with bavituximab," said Dr. Taha Merghoub.
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"We are delighted to be working with a world-renowned pioneer and leader in the immuno-oncology space, recognizing that there remains significant research in order for more cancer patients to realize the benefits of combination immune therapy," said Jeff T. Hutchins, PhD, VP of Preclinical Research at Peregrine. ”Our internal and collaborative research presented over the last year has established a robust foundation of PS-targeting activity on which to initiate this next chapter in PS research and development."
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"This collaboration is an important extension of our established research efforts to further explore and understand the potential of our PS-targeting platform including bavituximab our lead clinical candidate. This research will focus on better understanding how treatment with PS-targeting agents can assist other anti-tumor immunotherapies in order to work better," said Steven King, CEO of Peregrine. ”Our goal is to change the way cancer patients are treated by allowing their immune system to recognize and fight their disease. This collaboration will undoubtedly assist us in identifying potential new opportunities to better treat patients with cancer."
Dec7 2016: “Wistar Inst. Seminar - Combination Checkpoint Blockade”, Phila.
https://wistar.org/events/2016/12/combination-checkpoint-blockade
Lecture: Jedd D. Wolchok, MD/PhD, Chief of Melanoma & Immunotherapeutics Service at Memorial Sloan Kettering CC
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BAVI MOA 10-22-16: Duke’s Herbert K. Lyerly (w/PPHM) poster on AntiPS/TNBC data at AACR’s Tumor Immunotherapy Conf./Boston http://tinyurl.com/zzryfok
...”Modulating The Tumor Microenvironment to Enhance Cancer Immunotherapy by Inducing Phosphatidylserine Expression on the Tumor Surface”
BAVI MOA 9-27-16 AACR-CRI/Dr. Michael Gray: Preclin. Triple-Combo Bavi+PD1+LAG3 TNBC data in TNBC (80% Compl. Regression, Stat-Sig. Incr. in Key Tumor Fighting Immune Cells) http://tinyurl.com/zy9yv78
BAVI MOA 5-11-16 Breast Cancer Res. article, B.Freimark/CW.Hughes-et-al, “PS-Targeting/Bavi Combo w/Anti-PD1/PDL1 in Triple.Neg-MBC” http://tinyurl.com/zxu882y
...”our observations demonstrate that including PS-targeting antibodies such as bavituximab can enhance the anti-tumor activity of anti-PD-1/PD-L1 treatments, not only by increasing TIL responses but also by inhibiting cytokines stimulated by single-agent anti-PD-1 therapy that serve to suppress the immune response & promote tumor progression.”
BAVI MOA 4-20-16/AACR'16 & 4-4-16/Cancer-Immunology-Res.(AACR) article - preclin. data: Bavi combo w/anti-PD-1/anti-CTLA-4 “induces a shift in tumor microenvironment from immunosuppressive to immune active” http://tinyurl.com/jyox458
BAVI MOA 1-18-16: CEO Steve King explains PPHM's direct PS-Targeting advantage vs. the “individual-receptors” PS-binding approach of others like: Axl Mer TIM-3 RAGE Tyro3 GAS6 CD300a BAI1 MFG-E8 etc. http://tinyurl.com/h2h87mc
2-2016: Rutgers' Dr. Raymond Birge's relationship with Peregrine & UTSW's Dr. Rolf Brekken and his 2-26-16 article, “Phosphatidylserine is a Global Immunosuppressive Signal in Efferocytosis, Infectious Disease, and Cancer” http://tinyurl.com/z5d9qt9
11-9-15 SITC'15: New Bavi+Checkpoint Inhibitors preclin. data (UTSW/DUKE's Herbert K. Lyerly) http://tinyurl.com/pbof95w
...Also, collab. with Dr. Bernard Fox (Immunotherapist/Earle A. Chiles Res.Inst.) on new Immuno-Profiling Clinical Test (Opal 6-plex quantitative IF Assay), PPHM roundtable with Raymond Birge (Rutgers), Douglas Graham (Emory), Dmitry Gabrilovich (Wistar), Rolf Brekken (UTSW), Maria Karasarides (AstraZeneca) - ”Combining Bavi w/anti-PD-1 significantly enhanced O/S… significant incr. CD45+, CD8+ and CD3+ T-cells… led a prolonged anti-tumor immune response which protected the animals against a re-challenge w/same tumor.”
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
11-11-16:
11-11-16:
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]
11-14-16/PR: Dr. Jedd Wolchok: "Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model. It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact."
11-14-16/PR: Dr. Taha Merghoub (Co-Dir., Ludwig Collaborative Lab at MSK): "We have noted that the combination of PS-targeting treatment and radiation, as well as triple combination of PS-targeting treatment, radiation and anti-PD-1, resulted in clear advantages in anti-tumor activity in the mouse B16 melanoma model. We believe that these findings suggest the potential benefit of combining these agents to improve the outcomes of patients with cancer. With this in mind, we think this research may play an important role in designing future clinical trials of PS-targeting agents in melanoma and other cancers."
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11-14-16/PR: New Study Demonstrates Anti-Tumor Advantages for Combination Treatment Featuring Peregrine Pharmaceuticals' PS-Targeting Antibodies in a Preclinical Melanoma Model
* Promising Results of MSK Study Evaluating Combinations of PS-Targeting Treatment, Anti-PD-1 and Radiation in Mouse B16 Melanoma Model Presented at SITC 2016
* New Data from Second Study Conducted by Peregrine Shows Triple Combination of PS-Targeting Treatment, Anti-PD-1 and Anti-LAG3 Created Long-Term Immunity in Triple Negative Breast Cancer Model; Protected Animals when Re-Challenged with Breast Cancer Cells
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=999202
TUSTIN, Nov. 14, 2016: Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM/PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, today announced the presentation of positive data from multiple new preclinical studies of the company's phosphatidylserine (PS)-targeting antibodies. Study results highlight that PS-targeting antibodies similar to bavituximab synergize with checkpoint inhibitors and radiation to improve anti-tumor activity in various animal tumor models. Importantly, the improved anti-tumor activity seen in these studies was even greater when PS-targeting therapy was a part of triple combination treatment including anti-PD-1 and another therapy. Data were presented by Peregrine scientists, as well as researchers from Memorial Sloan Kettering Cancer Center (MSK), at the Society for Immunotherapy of Cancer (SITC) 2016 Annual Meeting, which was held November 9-13, 2016 in National Harbor, MD. [ http://www.sitcancer.org/2016 ]
Initial results from Peregrine's ongoing collaboration with MSK researchers were featured in a poster presented by Sadna Budhu, PhD, at SITC 2016. A team of MSK researchers led by cancer immunotherapy thought-leaders, Taha Merghoub, PhD and Jedd D. Wolchok, MD, PhD [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ], evaluated the effects of combining PS-targeting, anti-PD-1 and radiation therapies in the mouse B16 melanoma model. Study data showed that PS-targeting antibodies synergize with both anti-PD-1 and radiation therapy to improve anti-cancer activity. PS-targeting treatment in combination with radiation, as well as triple combination of PS-targeting treatment, anti-PD-1 and radiation, led to a reduction in tumor burden. Median survival for the triple combination treatment still had not been reached at the end of the 80-day observation period with other arms in the study showing median survival that ranged from 24-70 days.
Researchers also evaluated the impact of the PS-targeting and radiation combination treatment on the level and type of immune activity. These results demonstrated that the combination led to a change in the tumor microenvironment, shifting it from immunosuppressive in which tumors are protected to immune active in which tumors are more susceptible to treatment. Analysis of local immune responses in the tumors of the treated animals showed that the combination treatment increased the number of tumor associated macrophages and shifted the macrophage polarization from the immunosuppressive M2 type to the immune active M1 type. When systemic immune responses were analyzed following triple combination of PS-targeting treatment, anti-PD-1 and radiation, researchers also saw evidence of increased immune activity. This was illustrated by key indicators of immune activity, including increases in CD8+ T-cell activation, effector cytokine production and differentiation into effector memory cells.
"Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model," stated Dr. Jedd Wolchok. "It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact."
"We have noted that the combination of PS-targeting treatment and radiation, as well as triple combination of PS-targeting treatment, radiation and anti-PD-1, resulted in clear advantages in anti-tumor activity in the mouse B16 melanoma model," said Dr. Taha Merghoub, PhD, co-director of the Ludwig Collaborative Laboratory at MSK. "We believe that these findings suggest the potential benefit of combining these agents to improve the outcomes of patients with cancer. With this in mind, we think this research may play an important role in designing future clinical trials of PS-targeting agents in melanoma and other cancers."
[Note: FULL SITC’16 ABSTRACT #199: http://bit.ly/2dHTEVn
...Full Poster Image: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]
A second study, conducted by Peregrine, evaluated the effects of combining PS-targeting, anti-PD-1 and anti-LAG3 therapies in the E0771 triple negative breast cancer (TNBC) model. Initial findings from this study were previously reported and demonstrated that eight of the ten (80%) animals receiving the PS-targeting, anti-PD-1 and anti-LAG3 treatment combination experienced complete tumor regressions, whereas there were no animals (0/10) in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression. New data presented for the first time at SITC demonstrated that the triple combination established a specific and prolonged anti-tumor immune response which protected those eight animals that achieved a complete tumor regression against a re-challenge with the same E0771 TNBC model tumor cells. This sustained anti-tumor response demonstrates the ability of the triple combination treatment to trigger immune system memory and support adaptive immune responses against reemerging disease in the E0771 TNBC model.
[Note: FULL SITC’16 ABSTRACT #213: http://bit.ly/2dpUy4C ]
...Full Poster Image: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gray.pdf ]
Further highlighting the immune impact of the PS-targeting/anti-PD-1/anti-LAG3 treatment combination were initial results of a new analysis from this study using the nCounter ® PanCancer Immune Profiling Panel from NanoString Technologies ®. Data from the analysis demonstrated that the triple combination induced a greater shift in the tumor microenvironment from immunosuppressive to immune active as compared to all other treatment groups. This was evidenced by greater increases in the activity of several critical immune activating pathways, including presentation and processing of antigens and signaling and activation of T-cells, for the triple combination as compared to all other treatments.
"It is very encouraging to see the consistent increase in anti-tumor activity triggered by triple combination treatments that combine PS-targeting agents and anti-PD-1 with other cancer treatments. By demonstrating this activity across multiple studies in multiple tumor models, we are continuing to build scientific support for the therapeutic potential of adding PS-targeting therapies in combination with other cancer treatments, including checkpoint inhibitors such as anti-PD-1," said Jeff T. Hutchins, PhD, Peregrine's VP, Preclinical Research. "As cancer research continues to explore the potential of combination treatments that marry complementary mechanisms, we are pleased to see that our efforts continue to generate data supporting the role that PS-targeting agents such as bavituximab may play in this area."
Bavituximab is an investigational monoclonal antibody that targets PS. Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. Previous studies demonstrated PS-targeting antibodies shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor responses. Peregrine continues to support and guide clinical development through the evaluation of the preclinical equivalent of bavituximab, ch1N11, in animal model studies.
Peregrine's clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants awarded by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations [See: http://tinyurl.com/gutgwb5 ]. These trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination. Additionally, Peregrine continues to advance its pre-clinical collaboration with Memorial Sloan Kettering Cancer Center with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab's combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.
ABOUT PEREGRINE PHARMACEUTICALS, INC.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company committed to improving the lives of patients by delivering high quality pharmaceutical products through its contract development and manufacturing organization (CDMO) services and through advancing and licensing its investigational immunotherapy and related products. Peregrine's in-house CDMO services, including cGMP manufacturing and development capabilities, are provided 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. The company is also working to evaluate its lead immunotherapy candidate, bavituximab, in combination with immune stimulating therapies for the treatment of various cancers, and developing its proprietary exosome technology for the detection and monitoring of cancer. For more information, please visit http://www.peregrineinc.com .
Safe Harbor *snip*
Contacts:
Stephanie Diaz (Investors), Vida Strategic Partners, 415-675-7401, sdiaz@vidasp.com
Tim Brons (Media), Vida Strategic Partners, 415-675-7402, tbrons@vidasp.com
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iHub Poster FireFOX’s Commentary on the Joint MSKCC/PPHM SITC’16 News
11-15-16: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=126566507
SUBJ: IMPORTANCE OF WOLCHOK’S REMARKS IN YESTERDAY’S PR.
The key to partnerships comes from Wolchok’s confirmation that Bavi “creates a more immune active environment in which other treatments are able to have greater anti-tumor impact.”
Look how this remark echoes and reinforces comments by Dr. Perlmutter, head of IO research at Merck, in an October ESMO article on Keytruda vs. Opdivo. Dr. Perlmutter explained that higher levels of PD-L1 confer a greater benefit from PD-1 blockers and, “It turns out PD-L1 expression is just a marker for the presence of an immune response.” Here is a quote from the article:
“So what does PD-L1 expression mean — and why do higher levels confer a greater benefit from PD-1 blockers?
"It turns out PD-L1 expression is just a marker for the presence of an immune response," explained Merck's head of research, Dr. Roger Perlmutter. "Expression of PD-L1 is increased by immune response factors."
IN ENGLISH: PD-L1 is a signal that the immune system has been trying to fight the cancer. Or, as Perlmutter puts it, "Gee, there's already an immune response going on here."
http://www.cnbc.com/2016/10/07/bristol-myers-mercks-lung-cancer-treatments-square-off-this-weekend.html
This is why Wolchok’s comment yesterday is so important when he confirmed that Bavi’s MOA is to “create a more immune active environment”:
DR. JEDD WOLCHOK STATES (11-14-16), “Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model. It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact.
The really important part of the MSK poster, the part that will wake up all the BP decision makers, is not the mice survival data, but rather all the detailed work MSK did to confirm that Bavi is indeed triggering an upstream immune response, e.g. increase in CD8 T-cells, shift of macrophage from M2 to M1. MSK summarizes this “creation of a more active immune environment” in the 3rd & 4th bullet points of the Poster Conclusion. This is just what Dr. Perlmutter at Merck said was missing in the 80% of patients that don’t respond to PD-1. To quote Perlmutter, Keytruda & Opdivo work better when the clinician can say "Gee, there's already an immune response going on here."
There is now strong evidence from the MSK poster and Wolchok’s summary comments that Bavi triggers an upstream immune response. This will be a huge boost to the ongoing partnership talks. *end*
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MSKCC/Wolchok-Lab & PPHM, Nov11-12, Natl-HarborMD. 3 PS-Targeting/I-O Abstracts – note that the 1st one (#199 Nov. 11, 2016) is the joint MSKCC/PPHM one; its Senior author is Dr. Taha Merghoub (Jedd Wolchok Lab, Memorial Sloan Kettering), who said this in the 5-29-15 PPHM/MSK Collab. Announcement PR (see below): "A key focus of the Wolchok Lab's research is studying novel immunotherapy combinations that work together to enable the immune system to recognize & destroy cancer. This collaboration will allow us to focus on the role & contribution of PS blockade therapy in determining which combination of the current and next generation of immune modulators is likely to increase the extent and amplitude of anti-tumor response. This important pre-clinical & translational work will potentially guide the design of the next generation of clinical studies with bavituximab."
Nov9-13 2016: “(SITC) Society for Immunotherapy of Cancer 31st Annual Meeting”, Natl-Harbor MD
”The premier destination for scientific exchange, education, and networking in the Cancer Immunotherapy Field”
SITC = The Society for Immunotherapy of Cancer http://www.sitcancer.org
SITC 2016 Meeting: http://www.sitcancer.org/2016
Abstracts: http://www.sitcancer.org/2016/abstracts
PEREGRINE/MSKCC ABSTRACTS:
I. 11-11-16 12:15-1:30pm #199: “Phosphatidylserine Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma” - Sadna Budhu, PhD - Ludwig Collaborative Lab, MSKCC (Memorial Sloan Kettering)
AUTHORS: Sadna Budhu(MSKCC PRESENTING AUTHOR) 1, Olivier De Henau 2, Roberta Zappasodi 1, Kyle Schlunegger 3, Bruce Freimark 4, Jeff Hutchins 5, Christopher A. Barker 6, Jedd D. Wolchok 7, Taha Merghoub(MSKCC SENIOR AUTHOR) 1 [<=See 5-29-15 PPHM/MSKCC PR below]
1/2 Ludwig Collaborative Lab, Memorial Sloan Kettering CC, NYC
6 Memorial Sloan Kettering CC, NYC
7 Dept of Medicine, Memorial Sloan Kettering CC, NYC
3/4/5 Peregrine Pharmaceuticals, Tustin, CA
ABSTRACT: http://bit.ly/2dHTEVn POSTER PDF: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf
II. 11-12-16 11:45-1pm #210: “Antibody Targeting of Phosphatidylserine Enhances the Anti-Tumor Responses of Ibrutinib & anti-PD-1 Therapy in a Mouse Triple Negative Breast Tumor Model” - Jian Gong, PhD - Peregrine Pharmaceuticals
AUTHORS: Jian Gong, Michael Gray, Jeff Hutchins, Bruce Freimark - Peregrine Pharm. ABSTRACT: http://bit.ly/2dpUh1w POSTER PDF: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gong.pdf
III. 11-11-16 12:15-1:30pm #213: ”Monoclonal Antibodies Targeting Phosphatidylserine Enhance Combinational Activity of the Immune Checkpoint Targeting Agents LAG3 & PD-1 in Murine Breast Tumors” - Michael Gray, PhD - Peregrine Pharmaceuticals
AUTHORS: Michael Gray, Jian Gong, Jeff Hutchins, Bruce Freimark - Peregrine Pharm. ABSTRACT: http://bit.ly/2dpUy4C POSTER PDF: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gray.pdf
= = = = = = = = = = = =FULL ABSTRACTS:
http://resource-cms.springer.com/springer-cms/rest/v1/content/11027680/data/v1/Volume+4+Supplement+1+PDF+pt+2
I . #199/SITC’16/11-11-16(MSK+PPHM): “Phosphatidylserine Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma”
AUTHORS:
Sadna Budhu(MSKCC PRESENTING AUTHOR) 1, Olivier De Henau 2, Roberta Zappasodi 1, Kyle Schlunegger 3, Bruce Freimark 4, Jeff Hutchins 5, Christopher A. Barker 6, Jedd D. Wolchok 7, Taha Merghoub(Memorial Sloan Kettering SENIOR AUTHOR)
BACKGROUND:
Phosphatidylserine (PS) is a phospholipid that is exposed on the surface of apoptotic cells, some tumor cells and tumor endothelium. PS has been shown to promote anti-inflammatory and immunosuppressive signals in the tumor microenvironment. Antibodies that target PS have been shown to reactivate anti-tumor immunity by repolarizing tumor associated macrophages to a M1-like phenotype, reducing the number of MDSCs in tumors and promote the maturation of dendritic cells into functional APCs. In a B16 melanoma model, targeting PS in combination with immune checkpoint blockade has been shown to have a significantly greater anti-cancer effect than either agent alone. This combination was shown to enhance CD4+ and CD8+ T cell infiltration and activation in the tumors of treated animals. Radiation therapy is an effective focal treatment of primary solid tumors, but is less effective in treating metastatic solid tumors as a monotherapy. There is evidence that radiation induces immunogenic tumor cell death and enhances tumor-specific T cell infiltration in irradiated tumors. In addition, the abscopal effect, a phenomenon in which tumor regression occurs outside the site of radiation therapy, has been observed in both preclinical and clinical trials with the combination of radiation therapy and immunotherapy.
METHODS:
We examined the effects of combining tumor radiation therapy with an antibody that targets PS (1 N11) [Note: PGN635 (B2GPI-dep.) is Fully-Human Bavituximab=1N11=AT004; Genentech studying 89Zr-PGN635 as a Tumor Imaging Agent, “indep. of cancer type”] and an immune checkpoint blockade (anti-PD-1) using the mouse B16 melanoma model. Tumor surface area and overall survival of mice were used to determine efficacy of the combinations.
RESULTS:
We examined the expression of PS on immune cells infiltrating B16 melanomas. CD11b + myeloid cells expressed the highest levels of PS on their surface whereas T cells and B16 tumor cells express little to no PS. These data suggest that targeting PS in B16 melanoma would induce a pro-inflammatory myeloid tumor microenvironment. We hypothesize that therapies that induce apoptotic cell death on tumor cells would enhance the activity of PS-targeting antibodies. We therefore examined the effects of combining a PS-targeting antibody with local tumor radiation. We found that the PS-targeting antibody synergizes with both anti-PD-1 and radiation therapy to improve anti-cancer activity and overall survival. In addition, the triple combination of the PS-targeting antibody, tumor radiation and anti-PD-1 treatment displayed even greater anti-cancer and survival benefit.
CONCLUSIONS:
This finding highlights the potential of combining these 3 agents to improve outcome in patients with advanced-stage melanoma and may inform the design of future clinical trials with PS targeting in melanoma and other cancers *end*
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]
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II. #210/SITC’16/11-12-16(PPHM): “Antibody Targeting of Phosphatidylserine Enhances the Anti-Tumor Responses of Ibrutinib & anti-PD-1 Therapy in a Mouse Triple Negative Breast Tumor Model”
AUTHORS: Jian Gong, Michael Gray, Jeff Hutchins, Bruce Freimark - Peregrine Pharm.
BACKGROUND:
Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on vascular endothelial cells and tumor cells in the tumor microenvironment, particularly in response to chemotherapy and irradiation. Binding of antibodies targeting PS induces the recruitment of immune cells and engages the immune system to destroy tumor and associated vasculature and by blocking the immunosuppressive action of PS. Recent studies have demonstrated that PS-targeting antibodies enhance the anti-tumor activity of immune checkpoint antibody blockade to CTLA-4 and PD-1 in mouse breast and melanoma tumor models. Ibrutinib [Ibrutinib=Imbruvica, dev. by Pharmacyclics & J&J, acquired by ABBVIE in 2015, proj. global sales of $1B/2016, $5B/2020] is an approved anticancer drug targeting B cell malignancies that is a selective, covalent inhibitor Bruton's tyrosine kinase (BTK) in B cell tumors. Data from recent mouse tumor studies demonstrate that ibrutinib in combination with anti-PD-1 antibody blockade inhibits growth of solid tumors, lacking BTK expression, suggesting that ibrutinib may inhibit interleukin-2 inducible T cell kinase (ITK) and promote Th1 anti-tumor responses.
METHODS:
The present study was conducted to evaluate a combination therapy including PS-targeting antibody mch1N11, ibrutinib and anti-PD-1 antibody in C57Bl/6 mice bearing triple negative E0771 breast tumors. Tumors were staged to an initial volume of ~100 mm 3 and ran- domized to treatment groups (N=10) with mch1N11 or isotype control at 10 mg/kg qw, anti-PD-1 at 2.5 mg/kg qw or ibrutinib 6 mg/kg or vehicle qd x 8. Tumor volumes were measured twice per week to determine tumor growth inhibition (TGI) relative to control treated animals. The in vitro sensitivity of E0771 tumor cells to ibrutinib was compared to the drug sensitive Jeko-1 cell line in a 72 hour growth and viability assay.
RESULTS:
The E0771 cell line is resistant in vitro to 10 mM ibrutinib. Tumor bearing mice treated with mch1N11, ibrutinib or anti-PD-1 alone had 22.2 %, 23.5 % and 32.6 % TGI respectively. The TGI for mch1N11 and ibrutinib was 30.5 %, ibrutinib and anti-PD-1 was 34.5 %, mch1N11 and anti-PD-1 was 36.1 %. The triple combination therapy had statistically greater TGI compared to control treated mice (59.9 %, p = 0.0084).
CONCLUSIONS:
Treatment of solid tumors with a combination of inhibitors that target PS, ITK and the PD-1 D-L1 axis in the tumor microenvironment provides a novel treatment for solid tumors, including triple negative breast cancer. *end*
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gong.pdf ]
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III. #213/SITC’16/11-11-16(PPHM): ”Monoclonal Antibodies Targeting Phosphatidylserine Enhance Combinational Activity of the Immune Checkpoint Targeting Agents LAG3 & PD-1 in Murine Breast Tumors”
AUTHORS: Michael Gray, Jian Gong, Jeff Hutchins, Bruce Freimark - Peregrine Pharm.
BACKGROUND:
Our previous work demonstrated that the addition of phosphatidylserine (PS) targeting antibodies to anti-programmed death ligand 1 (PD-1) therapy in murine triple negative breast cancers (TNBC) significantly enhanced immune system activation and tumor growth inhibition. In these studies, NanoString immune profile analysis showed that intratumoral levels of lymphocyte activation ge ne 3 (LAG3) mRNA increased in response to PS and PD-1 treatments. This suggests LAG3 may act to attenuate T cell activation in TNBC du ring I/O therapeutic regimens; however, it is unknown if PD-1 and LAG3 function cooperatively in regulating T cell anergy, and whether adding PS blocking antibodies can further enhance the effectiveness of LAG3 and/or LAG3 + PD-1 therapies.
METHODS:
Animal studies utilized C57bl/6 mice implanted with the murine TNBC model E0771. Immunoprofiling analysis was performed by flow cytometry and the NanoString nCounter PanCancer Immune Profiling Panel. Antibody treatments utilized a specific phosphatidylserine targeting antibody (ch1N11), anti-PD-1, or anti-LAG3 alone or in combination. All statistical analysis utilized the student t-test (significant with p < 0.05). RESULTS: LAG3 and PD-1 were co-expressed on T cells in E0771. Mice treated with antibodies targeting PS, PD-1, and LAG3 alone in combination with each other demonstrated that the addition of PS blocking antibodies to anti-PD-1 therapy or LAG3 had significantly greater anti- tumor activity than either single agent. Comparison of PD-1 + LAG3 combinational therapy vs. single PD-1 or LAG3 treatments showed moderately more anti-tumor activity than single treatments; however, the addition of PS blocking antibodies to either checkpoint inhibitor was as equally effective in inhibiting tumor growth as observed in the combination of LAG3 + PD-1 treatment. Further comparison of PD-1 + LAG3 vs. PS + PD-1 + LAG3 treatments demonstrated that the addition of PS blocking antibodies resulted in a significant decrease in tumor growth accompanied by complete tumor regression in a greater number of animals than observed in the PD-1 + LAG3 treatment group. FACS and NanoString immunoprofiling analysis on each treatment group showed that the addition of PS blocking antibodies to all check- point treatment groups, including the combination of PD-1 + LAG3, resulted in enhanced tumor infiltrating lymphocytes (TILs), a reduction myeloid derived suppressor cells (MDSCs), and enhanced cytokines associated with immune system activation.
CONCLUSIONS Overall, our data demonstrate that while PS, LAG3, and PD-1 therapies each have efficacy in TNBC as single agents, I/O treatments that include PS blocking antibodies offer significantly improved growth inhibition and are capable of increasing TILs compared to single and combinational treatments by T cell checkpoint targeting inhibitors alone. *end*
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gray.pdf ]
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9-8-16/CC - JEFF HUTCHINS (VP/PreClinical Res.) http://tinyurl.com/jmy77g3
“...I would now like to provide an update on Peregrine's preclinical I-O focused internal efforts and our collaboration with Memorial Sloan Kettering Cancer Center. The goal of this work is to evaluate combinations of PS targeting with other checkpoint inhibitors and immune stimulatory agents for the purpose of developing new and increasingly effective anticancer treatments. These programs are advancing well and to-date, we have seen impressive signs of activity with new combinations of PS targeting and other treatment modalities such as checkpoint blockers, T-cell agonists and radiation. These new combinations are improving overall survival accompanied with increases in cyto-reactive T cells into the tumor tissue. This exciting new internal work will be presented at the AACR/CRI Immunotherapy Meeting in New York later this month [Sept25-28] and at ESMO in early October [Oct7-11: http://tinyurl.com/jxdppyo ]. We expect the first results from our collaboration with MSK’s Jedd Wolchok Lab investigators [See MSK Collab: http://tinyurl.com/zkvebh6 ] to be presented at SITC in November [Nov9-13: http://www.sitcancer.org/2016 Natl.Harbor MD] and we will provide more detailed information as that presentation becomes available.”
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5-29-15: Peregrine & Sloan Kettering Enter Collab. to “Investigate Novel PS-Targeting Immunotherapy Combos” http://tinyurl.com/o3k9ux8
...The studies at MSK will be performed under the direction of Taha Merghoub, PhD, [ http://www.mskcc.org/research-areas/labs/members/taha-merghoub-01 ] Associate Attending Biologist, Melanoma and Immunotherapeutics Service, Ludwig Collaborative and the Swim Across America Laboratory, a part of the laboratory of Jedd D. Wolchok, MD, PhD [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ], a leader in the field of cancer immunotherapy. Dr. Wolchok serves as the Chief, Melanoma and Immunotherapeutics Service, Lloyd J. Old Chair for Clinical Investigation as well as an Associate Director of the Ludwig Center for Cancer Immunotherapy at MSK.
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”The phosphatidylserine (PS) signaling pathway is a very interesting target for modulating the immune system's response to cancer. We look forward to exploring the potential of PS-targeting agents alone and with other immune modulators that may lead to novel advances in cancer therapy," said Dr. Jedd Wolchok.
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As part of the collaboration, researchers at MSK will conduct research to further explore the combination of PS-targeting agents, including bavituximab, that block a primary immunosuppressive pathway thereby allowing anti-tumor immune responses with other immuno-stimulatory agents that enhance immune responses. Specifically, MSK researchers will examine the combination of bavituximab alongside models of checkpoint blockade that are unresponsive to inhibition or co-stimulation given the ability of bavituximab to reprogram myeloid derived suppressor cells (MDSC) and increase tumoricidal T-cells in tumors, a mechanism of action that is complementary to checkpoint blockade and T-cell activation.
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"A key focus of the Wolchok Lab's research is studying novel immunotherapy combinations that work together to enable the immune system to recognize and destroy cancer. This collaboration will allow us to focus on the role and contribution of PS blockade therapy in determining which combination of the current and next generation of immune modulators is likely to increase the extent and amplitude of anti-tumor response. This important pre-clinical and translational work will potentially guide the design of the next generation of clinical studies with bavituximab," said Dr. Taha Merghoub.
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"We are delighted to be working with a world-renowned pioneer and leader in the immuno-oncology space, recognizing that there remains significant research in order for more cancer patients to realize the benefits of combination immune therapy," said Jeff T. Hutchins, PhD, VP of Preclinical Research at Peregrine. ”Our internal and collaborative research presented over the last year has established a robust foundation of PS-targeting activity on which to initiate this next chapter in PS research and development."
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"This collaboration is an important extension of our established research efforts to further explore and understand the potential of our PS-targeting platform including bavituximab our lead clinical candidate. This research will focus on better understanding how treatment with PS-targeting agents can assist other anti-tumor immunotherapies in order to work better," said Steven King, CEO of Peregrine. ”Our goal is to change the way cancer patients are treated by allowing their immune system to recognize and fight their disease. This collaboration will undoubtedly assist us in identifying potential new opportunities to better treat patients with cancer."
Dec7 2016: “Wistar Inst. Seminar - Combination Checkpoint Blockade”, Phila.
https://wistar.org/events/2016/12/combination-checkpoint-blockade
Lecture: Jedd D. Wolchok, MD/PhD, Chief of Melanoma & Immunotherapeutics Service at Memorial Sloan Kettering CC
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BAVI MOA 10-22-16: Duke’s Herbert K. Lyerly (w/PPHM) poster on AntiPS/TNBC data at AACR’s Tumor Immunotherapy Conf./Boston http://tinyurl.com/zzryfok
...”Modulating The Tumor Microenvironment to Enhance Cancer Immunotherapy by Inducing Phosphatidylserine Expression on the Tumor Surface”
BAVI MOA 9-27-16 AACR-CRI/Dr. Michael Gray: Preclin. Triple-Combo Bavi+PD1+LAG3 TNBC data in TNBC (80% Compl. Regression, Stat-Sig. Incr. in Key Tumor Fighting Immune Cells) http://tinyurl.com/zy9yv78
BAVI MOA 5-11-16 Breast Cancer Res. article, B.Freimark/CW.Hughes-et-al, “PS-Targeting/Bavi Combo w/Anti-PD1/PDL1 in Triple.Neg-MBC” http://tinyurl.com/zxu882y
...”our observations demonstrate that including PS-targeting antibodies such as bavituximab can enhance the anti-tumor activity of anti-PD-1/PD-L1 treatments, not only by increasing TIL responses but also by inhibiting cytokines stimulated by single-agent anti-PD-1 therapy that serve to suppress the immune response & promote tumor progression.”
BAVI MOA 4-20-16/AACR'16 & 4-4-16/Cancer-Immunology-Res.(AACR) article - preclin. data: Bavi combo w/anti-PD-1/anti-CTLA-4 “induces a shift in tumor microenvironment from immunosuppressive to immune active” http://tinyurl.com/jyox458
BAVI MOA 1-18-16: CEO Steve King explains PPHM's direct PS-Targeting advantage vs. the “individual-receptors” PS-binding approach of others like: Axl Mer TIM-3 RAGE Tyro3 GAS6 CD300a BAI1 MFG-E8 etc. http://tinyurl.com/h2h87mc
2-2016: Rutgers' Dr. Raymond Birge's relationship with Peregrine & UTSW's Dr. Rolf Brekken and his 2-26-16 article, “Phosphatidylserine is a Global Immunosuppressive Signal in Efferocytosis, Infectious Disease, and Cancer” http://tinyurl.com/z5d9qt9
11-9-15 SITC'15: New Bavi+Checkpoint Inhibitors preclin. data (UTSW/DUKE's Herbert K. Lyerly) http://tinyurl.com/pbof95w
...Also, collab. with Dr. Bernard Fox (Immunotherapist/Earle A. Chiles Res.Inst.) on new Immuno-Profiling Clinical Test (Opal 6-plex quantitative IF Assay), PPHM roundtable with Raymond Birge (Rutgers), Douglas Graham (Emory), Dmitry Gabrilovich (Wistar), Rolf Brekken (UTSW), Maria Karasarides (AstraZeneca) - ”Combining Bavi w/anti-PD-1 significantly enhanced O/S… significant incr. CD45+, CD8+ and CD3+ T-cells… led a prolonged anti-tumor immune response which protected the animals against a re-challenge w/same tumor.”
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
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