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MA11 - Biomarkers of IO Response (ID 912)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
MA11.01 - Comparative Efficacy of T-Cell Intrinsic Versus Extrinsic PD-1 Blockade to Overcome PD-L1+ Tumor-Mediated Exhaustion (ID 14194)
10:30 - 10:35 | Author(s): Nan Chen
Anti-PD-1 agents are effective in overcoming PD-L1+ mediated T-cell exhaustion. Effective therapeutic regimens include multiple, long-term administration. We hypothesized that a single dose of T-cell intrinsic PD-1 blockade by expression of a dominant negative receptor (PD1-DNR) can be equally effective as multiple doses of anti-PD-1 agent administration in the treatment of PD-L1 overexpressing thoracic cancers.a9ded1e5ce5d75814730bb4caaf49419 Method
Human T cells engineered to target the cancer-antigen mesothelin (MSLN) by expression of a chimeric antigen receptor (CAR) with or without co-transduction with a PD1-DNR underwent repeated antigen stress with cancer cells with constitutive overexpression of PD-L1. For comparative efficacy evaluation, anti-PD-1 antibody was co-administered with CAR T cells (CARs). In vitro efficacy was evaluated by cytotoxicity (chromium-51 release assay). In vivo, mice with established pleural tumor were treated with either a single dose of MSLN CARs (with and without anti-PD-1 agent) or MSLN PD1-DNR CARs. Tumor burden regression by bioluminescence imaging and median survival were evaluated.4c3880bb027f159e801041b1021e88e8 Result
In vitro, constitutive PD-L1 overexpression (Fig. A) inhibits MSLN CAR effector function as evidenced by a decrease in cytotoxicity following repeated stimulation with MSLN+PD-L1hi tumor cells (Fig B). MSLN PD1-DNR CARs had increased cytotoxicity when compared to MSLN CARs with or without high frequency anti-PD-1 antibody supplementation. In vivo, mice treated with MSLN CAR (with or without anti-PD-1 antibody) or MSLN PD1-DNR CARs demonstrated enhanced tumor regression (Fig C) and prolonged median survival (Fig D) compared to MSLN CARs alone. Furthermore, a single low dose of MSLN PD1-DNR CARs shows equal anti-tumor efficacy compared to MSLN CARs with multiple doses of anti-PD-1 antibody.
Our results demonstrate that CAR T cells engineered to express a cell-intrinsic PD-1 dominant negative receptor overcome PD-L1 mediated T-cell inhibition equally compared to multiple doses of anti-PD-1 antibody administration. A clinical trial with MSLN CAR PD1-DNR CAR T cells is being initiated.6f8b794f3246b0c1e1780bb4d4d5dc53
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