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4-4-16/Cancer-Immunology-Res.(AACR) article, “PS Blockade Enhances Antitumor Responses to CTLA-4 & PD-1 Antibodies in Melanoma” - Xianming Huang(UTSW/Brekken Lab), Bruce Freimark, Rolf Brekken(UTSW), 9 others…

4-4-16: “Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 & PD-1 Antibodies in Melanoma”
Cancer Research Institute Journal (AACR) – Rec.10-2-15, Rev.12-29-15, Acc.1-20-16, PubOnline=4-4-16
http://cancerimmunolres.aacrjournals.org/content/early/2016/04/02/2326-6066.CIR-15-0250.abstract
FULL(32pgs): http://cancerimmunolres.aacrjournals.org/content/early/2016/04/02/2326-6066.CIR-15-0250.full.pdf
Bruce D Freimark 1, Jian Gong 1, Dan Ye 2, Michael J. Gray 3, Van Nguyen 1, Shen Yin 1, Michaela M.S. Hatch 4, Christopher C W Hughes(PPHM SAB) 4, Alan J Schroit(PPHM SAB) 5, Jeff T Hutchins 1, Rolf A Brekken(PPHM SAB) 2, Xianming Huang 2
1 Preclinical Research, Peregrine Pharmaceuticals, Inc.
2 Hamon Ctr for Therapeutic Oncology Res., Depts of Surgery/Pharmacology, UTSW-MC/Dallas
3 Preclinical Research, Peregrine Pharmaceuticals
4 Molecular Biology & Biochemistry, Univ. of California, Irvine
5 Simmons Cancer Center, UTSW/Dallas
ABSTRACT
In tumor bearing animals, the membrane phospholipid phosphatidylserine (PS) suppresses immune responses, suggesting that PS signaling could counteract the antitumor effect of antibody-driven immune checkpoint blockade. Here we show that treating melanoma-bearing mice with a PS-targeting antibody enhances the antitumor activity of downstream checkpoint inhibition. Combining PS-targeting antibodies with CTLA-4 or PD-1 blockade resulted in significantly greater inhibition of tumor growth than did single agent therapy. Moreover, combination therapy enhanced CD4+ and CD8+ tumor-infiltrating lymphocyte numbers; elevated the fraction of cells expressing the pro-inflammatory cytokines IL2, IFNy, and TNFa; and increased the ratio of CD8 T cells to myeloid-derived suppressor cells and regulatory T cells in tumors. Similar changes in immune cell profiles were observed in splenocytes. Taken together, these data show that antibody-mediated PS blockade enhances the antitumor efficacy of immune checkpoint inhibition.
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IN SUMMARY(Pg.17): In summary, we have shown that PS-targeting antibodies improve the efficacy of anti-CTLA-4 or anti-PD-1 therapy in murine models of melanoma, suggesting that these combinations have the potential to improve outcome in patients with advanced stage melanoma. Bavituximab, a chimeric PS-targeting antibody, is currently being evaluated in late-stage clinical trials for the treatment of cancer patients with solid tumors (46,54) and strong antitumor activity has been demonstrated in melanoma clinical trials using checkpoint inhibitor antibodies targeting CTLA-4 (10), PD-1 (12,13), and PD-L1 (55). It is increasingly apparent that successful immunotherapy requires tumor cell killing, induction of pro-inflammatory immune responses and concomitant reduction of immunosuppressive signals leading to increased tumor infiltration by activated T cells. Based on the distinct mechanism of action and multiple points of blockade, PS-targeting antibodies such as bavituximab may enhance the anti-tumor responses of immune checkpoint inhibitors by further blocking suppressive signals in the tumor microenvironment.

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Apr17-20 2016: “AACR 2016”, New Orleans
http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=63
Abstracts: http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=63&DetailItemID=363
4-20-16/Wed. 7:30-11am, Session: IMMUNOMODULATION & IMMUNOTHERAPY
#5116: “Phosphatidylserine-Targeting Antibodies Augment Anti-Tumor Activity of PD-1 Antibodies and Alter Immuno-Profiles in Murine Triple Negative Breast Cancers”
Michael J. Gray 1, Jian Gong 1, Ryan N. Parks 1, Michaela M.S. Hatch 2, Van Nguyen 1, Christopher C.W. Hughes 2, Jeff T. Hutchins 1, Bruce D. Freimark 1
1=Peregrine Pharmaceuticals; 2=Univ. of Calif./Irvine
ABSTRACT: Current treatments for triple negative breast cancers rely primarily upon surgical intervention and chemotherapy. Unfortunately, chemotherapies have the propensity to help establish an immunosuppressive condition in part though exposure of phosphatidylserine (PS) in the tumor microenvironment. We demonstrate that treatment of the murine triple negative breast cancer E0771 using a PS-targeting antibody inhibits in vivo growth, and significantly enhances the anti-tumor activity of antibodies directed to the checkpoint inhibitor PD-1. Combinational treatment by antibodies targeting PS & PD-1 increased the number of tumor infiltrating lymphocytes (TILs) to a greater extent than observed with single-arm therapies. Furthermore, combination of PS & PD-1 targeting antibodies provides a distinct survival advantage over treatment by either agent alone, which correlates with an increase in complete tumor regression and the onset of a durable immune mediated response capable of rejecting a secondary challenge by the same tumor. Finally, immune-profiling analysis of tumor RNA using Nanostring revealed that the combination antibody therapy enhanced immune regulatory pathways including MHC class I/II expression, antigen processing and presentation, and leukocyte and macrophage functions. Combined, our data suggest that in triple negative breast cancers antibody therapy blocking PS-associated immunosuppression may further enhance immunotherapies directed at immune checkpoint inhibitors, including those targeting the PDL-1/PD-1 axis.
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Peregrine Exhibiting at Booth #2318 (across from MDAnderson #2312)
http://www.aacr.org/Documents/16AM_Exhibits_ListasofApr4.pdf (see rt.side bottom)

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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

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's 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