Patient-derived organoids as a potential model to predict response to PD-1/PD-L1 checkpoint inhibitors

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.

Generation and initial characterization of novel tumour organoid models to study human pancreatic cancer‐induced cachexia

“…18,24 Moreover, emerging evidence confirms the potential of tumour organoid-based high-throughput drug screens to identify novel targeted drugs and to predict patient treatment responses. 22,25,26 We therefore hypothesized that modelling human pancreatic cancer with organoids could represent a powerful novel approach to study direct cachexia-inducing properties of pancreatic cancer cells. The high efficiency with which primary tumour organoid cultures can be established in combination with thorough phenotyping of cachexia-related parameters of donor patients enables the application of organoids for understanding common cachexia-inducing mechanisms as well as interindividual differences.…”

A brief history of organoids

“…However, the fibroblasts and immune cells of these PDOs progressively decline over a 1- to 2-mo period, indicating that they can be used only for short-term disease modeling. Additionally, organoids generated from chordoma patients have also been shown to contain both PD-L1-positive tumor cells and PD-1/CD8-positive lymphocytes, and they displayed a marked response to nivolumab treatment ( 124 ). On the other hand, cocultures of PDOs and peripheral blood lymphocytes have also been explored to assess the efficiency of T cell-mediated killing of matched tumor organoids, whereas the coculture efficiency beyond 3 days has not been tested ( 26 ).…”

Exploration of Feasible Immune Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma Treatment in Real World Clinical Practice

“…This study successfully demonstrated heterogeneous distribution of PD-L1+ cells (determined by immunohistochemistry) in the tumor tissues. In addition, the response to nivolumab was also investigated by using this model [ 140 ].…”