Organoids to analyse the off-tumour toxicity of T-cell-engaging bispecific antibodies
December 2023
Roche Innovation Center Basel, Basel, Switzerland
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, it was shown 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 identify clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. The mechanisms of T-cell-mediated damage to neoplastic and donor-matched healthy epithelia at a single-cell resolution were analysed using multiplexed immunofluorescence. It was 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.
Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids
Nikolche Gjorevski
Added on: 02-16-2024
[1] https://www.nature.com/articles/s41551-023-01156-5
