TY - JOUR
KW - drug safety
KW - Immunotherapy
KW - intestinal stem cells
AU - Marius F. Harter
AU - Timothy Recaldin
AU - Regine Gerard
AU - Blandine Avignon
AU - Yannik Bollen
AU - Cinzia Esposito
AU - Karolina Guja-Jarosz
AU - Kristina Kromer
AU - Adrian Filip
AU - Julien Aubert
AU - Anneliese Schneider
AU - Marina Bacac
AU - Michael Bscheider
AU - Nadine Stokar-Regenscheit
AU - Salvatore Piscuoglio
AU - Joep Beumer
AU - Nikolche Gjorevski
AB - Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here we show that patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies (TCBs), and to capture clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. We analysed the mechanisms of T-cell-mediated damage of neoplastic and donor-matched healthy epithelia at a single-cell resolution using multiplexed immunofluorescence. We found that TCBs that target the epithelial cell-adhesion molecule led to apoptosis in healthy organoids in accordance with clinical observations, and that apoptosis is associated with T-cell activation, cytokine release and intra-epithelial T-cell infiltration. Conversely, tumour organoids were more resistant to damage, probably owing to a reduced efficiency of T-cell infiltration within the epithelium. Patient-derived intestinal organoids can aid the study of immune–epithelial interactions as well as the preclinical and clinical development of cancer immunotherapies.
BT - Nature Biomedical Engineering
DA - 2024-04
DO - 10.1038/s41551-023-01156-5
LA - en
N2 - Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here we show that patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies (TCBs), and to capture clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. We analysed the mechanisms of T-cell-mediated damage of neoplastic and donor-matched healthy epithelia at a single-cell resolution using multiplexed immunofluorescence. We found that TCBs that target the epithelial cell-adhesion molecule led to apoptosis in healthy organoids in accordance with clinical observations, and that apoptosis is associated with T-cell activation, cytokine release and intra-epithelial T-cell infiltration. Conversely, tumour organoids were more resistant to damage, probably owing to a reduced efficiency of T-cell infiltration within the epithelium. Patient-derived intestinal organoids can aid the study of immune–epithelial interactions as well as the preclinical and clinical development of cancer immunotherapies.
PY - 2024
SP - 345
EP - 360
T2 - Nature Biomedical Engineering
TI - Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids
UR - https://www.nature.com/articles/s41551-023-01156-5
VL - 8
Y2 - 2024-08-13
SN - 2157-846X
ER -