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A. Morello
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.11 - Mechanistic Insights into CAR T-Cell Efficacy in the Treatment of Heterogenous Antigen Expressing Lung Adenocarcinoma (ID 6039)
16:00 - 17:30 | Author(s): A. Morello
- Abstract
- Presentation
Background:
Our laboratory has translated (NCT02414269, NCT02792114) mesothelin (MSLN), a cancer-antigen, targeted chimeric antigen receptor (CAR) T-cell therapy to solid tumors including for lung adenocarcinoma (ADC) patients. The goal of this study is to investigate the anti-tumor efficacy of MSLN CAR T cells against lung ADC with heterogenous MSLN expression, and further develop mechanistic insights to potentiate the therapy.
Methods:
Human CAR T cells transduced with M28z, MSLN CAR with CD28 costimulation, were tested in vitro (cytotoxicity by [51]Cr release assay, proliferation, cytokine secretion, LFA-1/ICAM-1 [lymphocyte function associated antigen-1/intercellular adhesion molecule 1] adhesion assay, and flow cytometry) and in vivo (tumor and T-cell bioluminescence imaging [BLI], survival) against low-, high- or a mixture (50:50 or 70:30) of MSLN-expressing A549 human lung ADC.
Results:
MSLN CAR T cells demonstrate antigen-intensity dependant cytotoxicity against both low- and high- MSLN-expressing A549 cells with additive bystander cytotoxicity against [51]Cr-labelled low-MSLN A549 cells in the mixture both in vitro (Figure Panel A) and in vivo (22 days delay in tumor progression by low-MSLN A549 cells). Flow cytometry demonstrated ICAM-1 overexpression on low-MSLN A549 cells when treated with effector cytokine-rich supernatant collected by exposure of CAR T cells to high-MSLN A549 cells (Panel B), LFA-1 expression by MSLN-activated CAR T cells (Panel B). Activated CAR T cells adherence to ICAM-Fc coated plates compared to controls (Panel C). LFA-1/ICAM-1 expression promoted adherence of antigen-activated CAR T cells to low antigen-expressing tumor cells (Panel D), which is inhibited in the presence of LFA-1 blocking antibody (Panel E). Figure 1
Conclusion:
We provide a mechanistic reason for the antigen-specific, bystander efficacy of CAR T cells against low-antigen expressing lung cancer cells. Strategies to augment LFA-ICAM interactions between CAR T cells and cancer cells can effectively translate mesothelin-targeted CAR T-cell therapy against heterogenous antigen-expressing solid tumor, lung cancer.
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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
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
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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): A. Morello
- Abstract
- Presentation
Background:
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).
Methods:
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.
Results:
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
Conclusion:
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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