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AACR’15(Apr19-21), Peregrine’s 3 Abstracts: “PS targeting can override PS-mediated immunosuppression, reactivate innate tumor immunity, and evoke adaptive antitumor immunity”…

Apr18-22 2015: AACR 106th Annual Meeting, Phily http://www.aacr.org/2015
Abstracts: http://www.abstractsonline.com/plan/start.aspx
PEREGRINE’s Posters:
• Abstract #274(Apr19): “Bavituximab Modulates Tumor Microenvironment and Activates CD8+ Tumor Infiltrating Lymphocytes in a Patient-Derived 3D Ex-Vivo System of Lung Cancer”
• Abstract #252(Apr19): “Antibody-Mediated Phosphatidylserine Blockade Significantly Enhances the Efficacy Of Immune Checkpoint Blockades in K1735 & B16 Mouse Melanoma Models” [Bavi+Ipilimumab(BMS’s Yervoy)]
• Abstract #4289(Apr21): “Targeting of Phosphatidylserine by Monoclonal Antibodies Enhances the Activity of Immune Checkpoint Inhibitors in Breast Tumors”

Sun. Apr 19, 2015, 1-5pm, Abstract#274, Session: TUMOR MICROENVIRONMENT/INNATE IMMUNE ACTIVATORS
”Bavituximab Modulates Tumor Microenvironment and Activates CD8+ tumor Infiltrating Lymphocytes in a Patient-derived 3D Ex Vivo System of Lung Cancer”
Soner Altiok 1, Melanie Mediavilla-Valera 2, Jenny Kreahling 2, David Noyes 2, Tiffany N. Razabdouski 2, Nikoletta L. Kallinteris 3, Joseph Shan 3, Scott Antonia 2
1=Nilogen Oncosystems, Tampa, FL; 2=Moffitt CC/Tampa; 3=Peregrine Pharm.
ABSTRACT: Bavituximab is a monoclonal antibody directed against the membrane phospholipid phosphatidylserine exposed on the outer leaflet of tumor and vascular endothelial cells of the tumor microenvironment. Bavituximab modulates the tumor microenvironment by blocking PS-mediated immune suppression and activating cytotoxic T lymphocyte anti-tumor responses.
In this study, we tested the immunomodulatory effect of bavituximab using a proprietary 3D ex vivo tumor microsphere technology. Upon obtaining informed consent, fresh tumor tissue from lung cancer patients were collected at the time of surgical resection. Tissue was processed for characterization of the tumor microenvironment and potential immunosuppressive mechanisms such as expression of PD-1, CTLA4, LAG3, TIM3, BTLA, and Adenosine A2AR. 3D tumor microspheres were prepared and cells were treated ex vivo with f(ab)’2 version of bavituximab, bavituximab, docetaxel, and a combination of bavituximab and docetaxel for 36 hours within the 3D tumor microsphere simulating an intact tumor microenvironment made up of tumor infiltrating lymphocytes (TIL) and myeloid cells. At the end of the treatment, TILs were analyzed by flow cytometry for cell activation and changes in CD4, CD8 and Treg (CD25+/CD127-) subpopulations. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines, including human IFN-gamma in culture media as a surrogate of TIL activation.
Preliminary results indicate the combination of bavituximab & docetaxel can induce TIL activation as demonstrated by a significant increase in IFN-gamma secretion when compared to tumors treated with control or either agent alone. Flow cytometry analysis revealed that this effect was associated with low PD-1 expression on CD8 cells, but did not correlate with other known immune-modulating receptors.
This lung patient derived ex-vivo approach indicates that bavituximab in combination with docetaxel can elicit a tumor specific immune response in human adenocarcinoma of the lung. This effect involves, at least in part, activation of CD8+ TIL and increased inflammatory cytokine production by lymphoid and myeloid cells. In addition, we have observed low PD1 expression as a potential prognostic biomarker of positive response to bavituximab treatment.

Sun. Apr 19, 2015, 1-5pm, Abstract#252, Session: IMMUNE CHECKPOINTS
“Antibody-Mediated Phosphatidylserine Blockade Significantly Enhances the Efficacy of Immune Checkpoint Blockades in K1735 & B16 Mouse Melanoma Models”
Bruce Freimark 1, Jian Gong 1, Dan Ye 2, Rolf Brekken 2, Shen Yin 1, Jeff Hutchins 1, Van Nguyen 1, Chris Hughes 3, Xianming Huang 2
1=Peregrine Pharm.; 2=UTSW-MC/Dallas; 3=Univ. of Calif/Irvine
ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed abundantly on tumor endothelial cells, tumor-secreted microvesicles, and tumor cells in response to chemo- and radiotherapy. Extensive studies have shown that PS is a global immune checkpoint and major contributor to tumor immunosuppression, which promotes the expansion of immunosuppressive cells, such MDSC & M2 macrophages, inhibits DCs maturation, while stimulates them to secrete immunosuppressive mediators. We have shown that PS targeting can override PS-mediated immunosuppression, reactivate innate tumor immunity, and evoke adaptive antitumor immunity. In the present study, we assessed the antitumor effect of the combination of PS blockade and anti-CTLA-4 or anti-PD-1 antibodies in B16 & K1735 melanoma models. Both combinations showed significantly superior tumor growth inhibition over single treatment, with many mice achieving complete tumor regression. Flow cytometry analysis showed that the combination treatment had significantly greater total and functional tumor-infiltrating CD8+ T, more IL-2- and IFNy-producing splenic T cells, and lower number of splenic MDSCs than did single treatment. In addition, the ratio of M2 to M1 in the tumor was significantly lower in the combination treatment than that in single treatment. Finally, no toxicity was observed in any of the treatment groups following multiple treatment doses. These data suggest that combination of PS blockade with immune checkpoint blockade promotes strong, localized, enhanced therapeutic efficacy without the side-effects of systemic immune activation and represents a promising combinatorial strategy for cancer immunotherapy. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. These data support our Phase I IST evaluation of our PS-targeting antibody bavituximab in combination with ipilimumab in advanced melanoma patients.
NOTES:
Ipilimumab=BMS’s Yervoy (anti-CTLA-4) http://www.yervoy.com ]
O. PPHM’s 6th IST Trial: Bavi+Ipilimumab(Yervoy) vs. Adv.Melanoma (Ph1b, random, open-label, 2arms, n=24)
Protocol (UTSW): http://www.clinicaltrials.gov/ct2/show/NCT01984255 (PI: Dr. Arthur Frankel - see "Researching for Cures"

)
UTSW's listing: http://www.utsouthwestern.edu/research/fact/detail.html?studyid=STU%20102013-007
...4-23-14: Bavi+Yervoy IST trial initiated: http://tinyurl.com/km7krcm

Tue. Apr 21, 2015, 1-5pm, Abstract#4289, Session: NOVEL IMMUNOMODULATORS
”Targeting of Phosphatidylserine by Monoclonal Antibodies Enhances the Activity of Immune Checkpoint Inhibitors in Breast Tumors”
Jian Gong, Shen Yin, Van Nguyen, Jeff Hutchins, Bruce D. Freimark - Peregrine Pharm.
ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on tumor vascular endothelial cells (ECs) and tumor cells. PS exposure becomes enhanced in response to chemotherapy, irradiation, and oxidative stresses in the tumor microenvironment. PS exposure in tumors promotes an immunosuppressive microenvironment which includes the recruitment of myeloid derived suppressor cells (MDSCs), immature dendritic cells and M2-like macrophages, as well as, the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumor cells and their secreted microparticles triggers an Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses the immunosuppressive PS meditated checkpoint, thereby enhancing anti-tumor immunity. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using breast tumors in immune competent mice, we demonstrate PS targeting antibodies enhance the anti-tumor activity of combination therapies including anti-PD-1 antibodies. Tumor growth inhibition correlates with statistically significant increases in the infiltration of CD8+ T cells and a reduction of myeloid-derived suppressor cells (MDSCs). The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.