Avid Bioservices Inc (CDMO): The PPHM/DUKE(H.Lyerly) Collab: Oct’16,...

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Monday, 03/06/2017 3:09:58 PM

Monday, March 06, 2017 3:09:58 PM

The PPHM/DUKE(H.Lyerly) Collab: Oct’16, AntiPS+PDL1/TNBC, “Greater Anti-Tumor Responses”.
The Full Abstract from Dr. Lyerly’s 10-22-16 AACR/CRI Conf. Poster published 3-2017 in conf. proceedings. Conclusion: “PS expression is upregulated by chemotherapy, radiotherapy, and photodynamic therapy in vitro. A combination therapy of PS-targeting + Anti-PD-L1 appears superior to single agent therapy. Our future plan is to investigate the effect of local irradiation or photodynamic therapy combined with PS-targeting mAb & anti-PD-L1 Ab.”

Oct20-23 2016: “AACR’s Tumor Immunology & Immunotherapy Conf.”, Boston
http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=92
10-22-16 POSTER SESSION B: “Immunomodulation”
#B36 “Modulating The Tumor Microenvironment to Enhance Cancer Immunotherapy by Inducing Phosphatidylserine Expression on the Tumor Surface”
Kensuke Kaneko 1, Takuya Osada 1, Bruce D. Freimark 2, Herbert Kim Lyerly ** (Duke Univ.) 1
1=Duke University, Durham, NC
2=Peregrine Pharmaceuticals
**Dr. Herbert Kim Lyerly: https://immunology.duke.edu/people/herbert-kim-lyerly-md (Dept. of Immunology, George Barth Geller Professor, Duke Univ. MC; same dept. as Barton Haynes)
ABSTRACT (from Conf. Proceedings – pub. 3/2017):
http://cancerimmunolres.aacrjournals.org/content/5/3_Supplement/B36
BACKGROUND & HYPOTHESIS:
While immune checkpoint blockade, in particular PD-1 or PD-L1 inhibition, has revolutionized cancer immunotherapy, a significant number of patients with solid tumors fail to respond to therapy. An emerging consensus is the need for a local infiltration of immune effector T cells, in combination with PD-1 or PD-L1, for anticancer responses. We are exploring an improved strategy to modulate the tumor microenvironment by targeting phosphatidylserine (PS), which is a phospholipid membrane component maintained on the cytosolic side of the cell membrane in viable cells. When a cell undergoes apoptosis or stress induced by the microenvironment, PS is no longer restricted to the cytosolic domain and gets transposed to the extracellular surface where it serves a variety of functions, including as a ligand for another immune checkpoint, TIM-3. In fact, PS-targeting antibodies induce immunity against weakly immunogenic tumor cells (He at al, 2009), and may serve to enhance anti-cancer immunotherapy. Chemotherapy and radiation therapy are often used to treat cancers. In addition, photodynamic therapy using a photosensitizer conjugated with a target specific molecule has been recognized as an emerging therapeutic strategy. Therefore, we sought to determine the expression of PS following treatment with chemotherapy, radiation, or photodynamic therapy, and to determine if the addition of a PS-targeting antibody could augment antitumor response, especially in combination with PD-1 inhibition.
METHODS & RESULTS:
We first confirmed the upregulation of PS on malignant human cells following treatment with chemotherapy by FACS analysis using PS-targeting antibody mch1N11 [“Mouse version of Bavituximab”]. PS expression was increased (50.2% positive compared to 5.0% in untreated cells) after 18 h of incubation with etoposide (25uM). We then tested PS expression on murine triple negative breast cancer cell lines (E0771-OVA, 4T1) at days 1, 2, and 4 after a single dose of X-ray (30, 40, or 50 Gy). E0771-OVA cells showed increased PS expression at day 2, while 4T1 cell lines increased PS expression at day 4. E0771-OVA cells were also irradiated using a more conventional schedule, specifically daily administration (6 Gy/day 5 days), leading to increase PS expression. Additionally, we tested PS expression on E0771-OVA cells after photodynamic therapy using HS201, which is a synthesized photosensitizer compound constructed of verteporfin and HSP 90 inhibitor. PS expression increased at day 1 when the cells were treated with a single dose of laser (10 or 60J) after 30 minutes conjugation of HS201 (1 or 10 uM). After confirming upregulation of PS by chemotherapy, radiotherapy, and photodynamic therapy, we next tested the combination of PS-targeting mAb mch1N11 with chemotherapy in vivo. We treated C57BL/6 mice bearing E0771-OVA tumors with paclitaxel (PTX), PS-targeting mAb mch1N11, anti-PD-L1 Ab, or combination. As single agents, both mch1N11 & anti-PD-L1 mAbs showed tumor growth suppression; however, combination of those 2 and 3 combination showed stronger effect. On the other hand, PTX didn't seem to add any additional effect.
CONCLUSIONS:
PS expression is upregulated by chemotherapy, radiotherapy, and photodynamic therapy in vitro. A combination therapy blocking PS by PS-targeting mAb and immune checkpoint blockade with anti-PD-L1 mAb appears superior to single agent therapy. Our future plan [a/o 10-22-16] is to investigate the effect of local irradiation or photodynamic therapy combined with PS-targeting mAb & anti-PD-L1 Ab.
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10-22-16: Duke’s Herbert K. Lyerly (w/PPHM) poster on AntiPS/TNBC data at AACR’s Tumor Immunotherapy Conf./Boston - ”Modulating The Tumor Microenvironment to Enhance Cancer Immunotherapy by Inducing Phosphatidylserine Expression on the Tumor Surface” http://tinyurl.com/zzryfok
From the PPHM PR: “Peregrine… announced the presentation of preclin. study data demonstrating that PS-targeting antibodies similar to bavituximab are able to enhance the anti-tumor activity of anti-PD-L1 therapy in a model of triple neg. breast cancer (TNBC). Data showed that a combination of anti-PS & anti-PD-L1 therapies, with or without paclitaxel, led to greater anti-tumor responses than any of the treatments administered as single agents or dual treatment combinations with paclitaxel, in the well-characterized E0771 murine model of TNBC. Study results were presented by researchers from Duke University Medical Center [Senior Author: Dr. Herbert Kim Lyerly] at the AACR’s “Tumor Immunology & Immunotherapy Conf.”, Oct. 20-23, 2016 in Boston.
In addition to evaluating the anti-tumor activity of the various treatment combinations, researchers also examined the impact of various traditional cancer therapies on PS expression in cancer cells. Study results confirmed that levels of PS expression were upregulated in E0771 & 4T1 TNBC cells following treatment with chemotherapy, radiation or photodynamic therapy. Photodynamic therapy also was shown to increase PS expression on tumor cells.
DR. JEFF HUTCHINS(VP/Preclin.):
"These study results provide the latest support for the belief that PS-targeting therapies can enhance the anti-tumor activity of checkpoint inhibitors such as anti-PD-L1 therapy in the treatment of TNBC. Just last month [9-27-16 AACR/CRI: http://tinyurl.com/zy9yv78 ], we announced results from another preclinical study in TNBC demonstrating that 80% of animals receiving the triple combination of anti-PS, anti-PD-1 and anti-LAG3 therapies experienced complete tumor regressions, whereas there were no animals in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression. Additionally, these latest study findings related to increased PS expression on the surface of tumor cells following traditional cancer treatments demonstrate important activity within the tumor microenvironment that offers rationale for the potential of anti-PS agents in combating cancer. We plan to continue to work with our collaborators at Duke University Medical Center to further study the therapeutic potential of PS-targeting agents in combination with checkpoint inhibitors like anti-PD-L1 and conventional therapies that augment immunotherapy mechanisms."
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RECALL:
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.”