PD-L1 Tumour Expression Hard to Quantify

Programmed death-ligand 1 quantification complicated by heterogeneous expression in tumours and inter-test variability

medwireNews: Research has highlighted difficulties with measuring programmed death-ligand 1 (PD-L1) expression as a predictor of non-small-cell lung cancer (NSCLC) response to treatments targeting programmed cell death protein 1 (PD-1).

“Our results suggest that PD-L1 protein expression is heterogeneous and that different antibody assays may yield discordant results”, say David Rimm, from Yale University School of Medicine in New Haven, Connecticut, USA, and co-authors.

Quantitative immunofluorescence testing of 49 NSCLC samples using two different monoclonal antibodies against PD-L1 showed that 26.6% of patients who tested positive for one antibody were negative for the second, the team reports.

“This is concerning because PD-L1 antibodies and platforms used by pharmaceutical companies for their clinical trials are proprietary, and thus, there is no opportunity for comparison between methods or reagents”, the researchers explain.

In addition, traditional immunohistochemistry testing showed significant intra-assay heterogeneity in the tumour samples.

And there was poor concordance for immunohistochemistry using the two different antibodies despite both reportedly binding to the same intracellular domain on PD-L1.

This may be caused by different antibody affinities, poor specificity or binding to distinct epitopes, explain David Rimm et al, who suggest that “antibody validation data should be shown in future clinical trial reports.”

They therefore conclude in JAMA Oncology: “Determination of the optimal assay, PD-L1 antibody, and the best cut-point for PD-L1 positivity, will require further rigorous studies including tissues with known response to anti–PD-1 and anti–PD-L1 therapies.”

The authors of an accompanying comment emphasise that individualised therapy relies on the ability to predict which patients will respond to therapy targeting PD-L1.

“As a biomarker, however, PD-L1 immunohistochemistry offers poor sensitivity and reproducibility, and as a result, these patients may be unfairly excluded from clinical trials”, caution Robert Anders, from Johns Hopkins University in Baltimore, Maryland, USA, and Feriyl Bhaijee, from AmeriPath Indiana in Indianapolis, USA.

“To offer this potentially life-saving personalized immune-based therapy to as many patients as possible, we need to develop a multifaceted predictive biomarker system that integrates checkpoint inhibitors such as PD-L1, tumor mutations, and inflammatory cells”, they say.


McLaughlin J, Han G, Schalper KA, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol 2015; Advance online publication 12 November.doi:10.1001/jamaoncol.2015.3638

Bhaijee F, Anders RA. PD-LA expression as a predictive biomarker. Is absence of proof the same as proof of absence? JAMA Oncol 2015; Advance online publication 12 November.doi:10.1001/jamaoncol.2015.3782

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