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M. Sadelain

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    OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      OA02.06 - Converting Tumor-Mediated PD-L1 Inhibition into CAR T-Cell Costimulation to Potentiate Thoracic Cancers Immunotherapy (ID 6058)

      11:00 - 12:30  |  Author(s): M. Sadelain

      • Abstract
      • Presentation
      • Slides

      To overcome tumor-mediated inhibition of chimeric antigen receptor (CAR) T cells, we herein investigated the impact of tumor PD-L1 upregulation on CAR T-cell exhaustion and anti-tumor efficacy, and further developed clinically translatable T-cell extrinsic as well as intrinsic strategies to overcome PD-L1 inhibition in models of lung cancer (LC) and malignant pleural mesothelioma (MPM).

      Human T cells were transduced with MSLN-specific CAR with CD28 and CD3zeta domains (M28z) were tested in vitro and in clinically-relevant LC and MPM mouse models by bioluminescence imaging, BLI of tumor burden progression. To counteract PD-1/PD-L1 inhibition in vivo, we evaluated the efficacy of PD-1 blocking antibody or cell-intrinsic genetic-engineering strategies by cotranducing M28z CAR T cells with a PD-1 dominant negative receptor (PD1-DNR) or with PD-1/4-1BB fusion protein.

      A single, low-dose of M28z CAR T cells is able to resist the progression of established tumor for 40 days, but mice eventually died with progressing tumor. Tumor harvest analysis demonstrated the PD-1 and PD-L1 upregulation on CAR T cells and tumor cells (Figure panel A). We then confirmed in vitro that PD-L1 inhibits M28z T-cell effector functions (proliferation, cytotoxicity and cytokine secretion). The addition of PD-1 blocking potentiates CAR T-cell therapy in vivo but its efficacy requires multiple injections (Panel B). In contrast, a single dose of M28z T cells coexpressing PD1-DNR restore effector functions, enhance tumor burden control (Panel C) and prolong median survival (56 vs 82 days, p=0.001). Converting PD-L1 inhibition into a positive costimulatory signal by PD-1/4-1BB construct cotransduction into M28z CAR T cells enhanced cytokine secretion and T-cell accumulation (Panel D). Figure 1

      Our results demonstrate the therapeutic benefit of providing optimal costimulation and coinhibitory blockade to counteract PD-L1/PD-1 immunosuppression, thus potentiate CAR T-cell therapy for lung cancer and mesothelioma.

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