Abstract
Anti‐PD‐1/PD‐L1 immunotherapy could offer an alternative to traditional chemo‐ and/or radiotherapy to treat pediatric cancer patients. To unveil the potential benefit of this new therapeutic approach, the prevalence of PD‐L1 and other relevant immune markers using quantitative digital image analysis (DIA) could help to clarify this point. A bridging study was first conducted using commercially available normal formalin‐fixed paraffin‐embedded (FFPE) tonsils to compare immunostaining patterns and intensities from PD‐L1, tumor infiltrating lymphocyte (TIL) markers CD3, CD8, FoxP3, CD45RO, and macrophage marker CD68 in adult (n = 5) and pediatric (n = 10) samples. Then, commercially available pediatric FFPE tumor samples from five prevalent pediatric solid tumor indications: ganglioneuroblastoma (n = 7); neuroblastoma (n = 23); nephroblastoma (n = 30); osteosarcoma (n = 24); and rhabdomyosarcoma (n = 25) were immunostained and their images (n = 654) digitally analyzed using predefined algorithms. The qualitative analysis of staining patterns and intensities in all 15 tonsils for all 6 biomarkers was similar regardless of age category. Quantitative DIA showed that PD‐L1 values varied across cancer‐types, nephroblastoma having the lowest counts. PD‐L1 counts in ganglioneuroblastoma, our pediatric indication with the highest average value, was approximately 12‐times lower than in a similar nonsmall cell lung cancer study, an indication approved for anti‐PD‐1/PD‐L1 immunotherapies. Variable values were measured for the TIL markers CD3, CD8, and CD45RO. FoxP3 was scant across all indications. The macrophage marker CD68 showed highest values in ganglioneuroblastoma, with lowest levels in nephroblastoma. In conclusion, the low PD‐L1 levels uncorrelated with TIL values from the present biomarker morphological study suggest that a PD‐L1 immunohistochemistry patient selection strategy used for anti‐PD‐1/PD‐L1 monotherapy in adult tumors may not succeed in these pediatric indications.
Highlights
Pediatric oncology has seen great improvements in mortality and survival rates among children and adolescents due to the optimization of targeted combination chemotherapy, especially in hematological malignancies [1,2]
PD-L1 counts in ganglioneuroblastoma, our pediatric indication with the highest average value, was approximately 12-times lower than in a similar nonsmall cell lung cancer study, an indication approved for anti-PD-1/PD-L1 immunotherapies
Evaluated were 109 pediatric surgical samples diagnosed with ganglioneuroblastoma, neuroblastoma, nephroblastoma, osteosarcoma, and rhabdomyosarcoma, which were collected before chemo/radiotherapy treatment
Summary
Pediatric oncology has seen great improvements in mortality and survival rates among children and adolescents due to the optimization of targeted combination chemotherapy, especially in hematological malignancies [1,2]. Novel treatment options like anti-PD-1/PD-L1 checkpoint inhibitors could offer a therapeutic alternative to fulfill the current needs [5,6]. Such biologicals have been approved for the treatment of a variety of adult tumor types, unleashing antitumoral T-cell adaptive immune responses. No targeted PD-1/PD-L1 clinical trial has yet been completed, a phase I/II pediatric study performed in patients refractory to available treatments using the anti-PD-1 mAb Pembrolizumab showed a 8–9% overall response rate [9,10], pointing out recent progress for checkpoint inhibitors in pediatric oncology
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