A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma.
Clin Cancer Res
; 28(3): 518-525, 2022 02 01.
Article
en En
| MEDLINE
| ID: mdl-34785583
ABSTRACT
PURPOSE:
Less than 50% of patients with melanoma respond to anti-programmed cell death protein 1 (anti-PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti-PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti-PD-1 therapy. EXPERIMENTALDESIGN:
PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n = 66 and validation n = 71) of samples from patients with melanoma treated with anti-PD-1±anti-CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8+ cells density, and NanoString RNA signature, were also evaluated.RESULTS:
A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71-0.77). Progression-free and overall survival were significantly longer in patients with high PLA values (P = 0.00019 and P < 0.0001, respectively).CONCLUSIONS:
The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti-PD-1 efficacy.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Protocolos de Quimioterapia Combinada Antineoplásica
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Biomarcadores de Tumor
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Anticuerpos Monoclonales Humanizados
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Antígeno B7-H1
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Receptor de Muerte Celular Programada 1
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Ipilimumab
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Nivolumab
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Inhibidores de Puntos de Control Inmunológico
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Melanoma
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article