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T.N. Razabdouski



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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.07 - Bavituximab Activates CD8+ TILs in a 3D Ex Vivo System of Lung Cancer Patients Derived Tumors With Negative PD-L1 Expression (ID 2162)

      11:20 - 11:25  |  Author(s): T.N. Razabdouski

      • Abstract
      • Presentation
      • Slides

      Background:
      Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Bavituximab blocks PS-mediated immune suppression and activates cytotoxic T lymphocyte anti-tumor responses.

      Methods:
      Tissues from consented patients with adenocarcinoma of the lung were extracted at the time of surgical resection and disaggregated to characterize expression of immune checkpoint proteins such as PD-1, CTLA-4, LAG3, TIM3, BTLA and adenosine A2A receptor on both CD4+ and CD8+ tumor infiltrating cells by flow cytometry (FACS) and stained for PD-L1, CD68, and CD163 via immunohistochemistry (IHC). 3D tumor microspheres were prepared and treated ex vivo with an IgG control, F(ab)’2 version of bavituximab, bavituximab, docetaxel, anti-PD-1 or PD-L1 and combinations of bavituximab, anti-PD-1 or PD-L1 and docetaxel for 36 hours within an intact tumor microenvironment. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by treatment. In a few cases, the expanded TILs were tested in PDX models using the consented patient’s tumor.

      Results:
      Bavituximab induces activation of TILs in 3D ex vivo tumor microsphere models of lung cancer, as demonstrated by a significant increase in IFN-ɣ, TNF-a, and GM-CSF secretion. FACS, IHC, and NanoString gene function analysis read out assays revealed that this effect was associated with low PD-1 expression on CD8+ cells, negative PD-L1 expression in the stating biopsy tissue, and a conversion of the M2 to M1 macrophage phenotype.

      Conclusion:
      These data support the use of bavituximab as an immunomodulatory treatment in adenocarcinoma of the lung by enhancing the activation of CD8+ TIL derived from patients' tumors with negative PD-L1 expression; correlating with increased cytokine production by lymphoid cells and repolarization of myeloid cells from an immunosuppressive to an immune active state.

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