The advent immune checkpoints inhibitors as powerful therapeutics in oncology has been demanding the development and validation of biomarkers of response and disease course in cancer immunotherapy. Tumor PD-L1 expression by IHC has been linked to responses to anti-PD-L1 antibody treatment. Accordingly, the measure PD-L1 expression by IHC assay has been approved by the FDA as companion diagnostic, or as a complementary diagnostic in a variety of cancers. However, IHC may be an insensitive measure of tumor PD-L1 expression, and it is conceivable that incomplete tumor sampling may mischaracterize PD-L1–positive tumors as negative. Moreover, IHC is not suitable for the dynamic evaluation of immune status and response to treatment. We developed in-house sandwich ELISA for serum PD-L1 (sPD-L1) detection, with a linear range of 0.4–50.0 ng/mL and intra/inter- assay CV% < 10%. Spike recovery and linear dilution analysis revealed a higher accuracy of our in-house ELISA when compared two commercial ELISAs. The mean sPD-L1 level of healthy blood donors was 0.67 ng/ml (range 0.09 – 3.50 ng/ml: 95% CI: 0.39 to 0.45 ng/ mL). Predictive value of sPD-L1 was evaluated in a cohort of cancer patients treated with PD-L1 inhibitors (n=20, 7 ADK lung; 4 Mel; 1 Merkel; 8 SQ lung) with respect to Progression-Free Survival (PFS) and Overall Survival (OS). Baseline sPD-L1 levels in cancer patients was 4.83 ng/ml (range 0.76 – 11.30 ng/ml: 95% CI: 3.29 to 6.36 ng/dL), which tested significant as compared to healthy donors group (P<0.0001). Then, we used the median value of sPD-L1 concentrations in the samples of study cohort as a cut-off to divide two groups: low (< 4.6 ng/dL) and high (sPD-L1 ≥ 4.6 ng/dL) sPD-L1. Patients with high sPD-L1 levels (sPD-L1 ≥ 4.6 ng/mL) showed an improved PFS (HR 0.31) and OS (HR 0.19) as compared to the low sPD-L1 group (sPD-L1 ≥ 4.6 ng/dmL). Our exploratory analysis supports a promising role for sPD-L1 detection as biomarker of response for anti-PD-L1 immunotherapy. Different ELISAs showed significant analytical bias with possible clinical implications for the interpretation of the sPD-L1 results, which demands for efforts to harmonize the sPD-L1 detection across manufacturers.

Serum Programmed death-ligand 1 (PD-L1) as biomarker or response for anti-PD-L1 immunotherapy

Trimboli F;Mimmi S;Tassone P;Palmieri C.
2018-01-01

Abstract

The advent immune checkpoints inhibitors as powerful therapeutics in oncology has been demanding the development and validation of biomarkers of response and disease course in cancer immunotherapy. Tumor PD-L1 expression by IHC has been linked to responses to anti-PD-L1 antibody treatment. Accordingly, the measure PD-L1 expression by IHC assay has been approved by the FDA as companion diagnostic, or as a complementary diagnostic in a variety of cancers. However, IHC may be an insensitive measure of tumor PD-L1 expression, and it is conceivable that incomplete tumor sampling may mischaracterize PD-L1–positive tumors as negative. Moreover, IHC is not suitable for the dynamic evaluation of immune status and response to treatment. We developed in-house sandwich ELISA for serum PD-L1 (sPD-L1) detection, with a linear range of 0.4–50.0 ng/mL and intra/inter- assay CV% < 10%. Spike recovery and linear dilution analysis revealed a higher accuracy of our in-house ELISA when compared two commercial ELISAs. The mean sPD-L1 level of healthy blood donors was 0.67 ng/ml (range 0.09 – 3.50 ng/ml: 95% CI: 0.39 to 0.45 ng/ mL). Predictive value of sPD-L1 was evaluated in a cohort of cancer patients treated with PD-L1 inhibitors (n=20, 7 ADK lung; 4 Mel; 1 Merkel; 8 SQ lung) with respect to Progression-Free Survival (PFS) and Overall Survival (OS). Baseline sPD-L1 levels in cancer patients was 4.83 ng/ml (range 0.76 – 11.30 ng/ml: 95% CI: 3.29 to 6.36 ng/dL), which tested significant as compared to healthy donors group (P<0.0001). Then, we used the median value of sPD-L1 concentrations in the samples of study cohort as a cut-off to divide two groups: low (< 4.6 ng/dL) and high (sPD-L1 ≥ 4.6 ng/dL) sPD-L1. Patients with high sPD-L1 levels (sPD-L1 ≥ 4.6 ng/mL) showed an improved PFS (HR 0.31) and OS (HR 0.19) as compared to the low sPD-L1 group (sPD-L1 ≥ 4.6 ng/dmL). Our exploratory analysis supports a promising role for sPD-L1 detection as biomarker of response for anti-PD-L1 immunotherapy. Different ELISAs showed significant analytical bias with possible clinical implications for the interpretation of the sPD-L1 results, which demands for efforts to harmonize the sPD-L1 detection across manufacturers.
2018
pd-l1; immunotherapy; peptide
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12317/58329
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