Abstract
Selection of cancer patients for treatment with immune checkpoint inhibitors remains a challenge due to tumour heterogeneity and variable biomarker detection. PD-L1 expression in 24 surgical chordoma specimen was determined immunohistochemically with antibodies 28-8 and E1L3N. The ability of patient-derived organoids to detect treatment effects of nivolumab was explored by quantitative and qualitative immunofluorescence and FACS analysis. The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1–15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.
Highlights
Immunotherapies targeting the programmed cell death-1 receptor (PD-1) and its ligand-1 (PD-L1) yielded impressive clinical results in advanced cancers expressing high levels of PDL1.1,2 novel treatments for rare cancers are limited by insufficient patients and trials to establish treatment benefits
Clinical trials evaluated the efficacy of targeting the PD-L1 axis with nivolumab alone or in combination with ipilimumab[8] and a trial combining nivolumab with stereotactic radiosurgery is ongoing (NCT02989636), but no data have yet been published on the correlation of PD-L1 expression and outcomes
The present results confirm the limitations of detecting PD-L1 by immunohistochemistry to select patient sensitive to nivolumab treatment
Summary
Immunotherapies targeting the programmed cell death-1 receptor (PD-1) and its ligand-1 (PD-L1) yielded impressive clinical results in advanced cancers expressing high levels of PDL1.1,2 novel treatments for rare cancers are limited by insufficient patients and trials to establish treatment benefits. This is true for chordomas, rare malignant tumours predominantly located in the spinal axis with a high local recurrence rate (43–85%) and a low tendency for distant metastasis.[3] Chordomas are resistant to chemotherapy (standard treatment: surgery and carbon ion–radiotherapy4), and are candidates for immunotherapy because they express more PD-1/PD-L1 than healthy bone tissues.[5,6,7] Clinical trials evaluated the efficacy of targeting the PD-L1 axis with nivolumab alone or in combination with ipilimumab[8] and a trial combining nivolumab with stereotactic radiosurgery is ongoing (NCT02989636), but no data have yet been published on the correlation of PD-L1 expression and outcomes. Because the potential advantages of organoids over cancer cell cultures are increasingly recognised,[9,10] we generated patient-derived organoids and determined the dose-dependent effects of nivolumab by quantifying diameters, apoptosis, and PD-L1 expression, to establish the potential of this approach for the prediction of treatment responses
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