02382nas a2200385   4500000000100000000000100001008004100002260001200043653001600055653001800071653002600089100002100115700002100136700001800157700002100175700001800196700002000214700002500234700002000259700001700279700001800296700002400314700001700338700002200355700003000377700002500407700001600432700002300448245013300471856005500604300001200659490000600671520130500677022001401982       2024                            d  c2024-0410adrug safety10aImmunotherapy10aintestinal stem cells1 aMarius F. Harter1 aTimothy Recaldin1 aRegine Gerard1 aBlandine Avignon1 aYannik Bollen1 aCinzia Esposito1 aKarolina Guja-Jarosz1 aKristina Kromer1 aAdrian Filip1 aJulien Aubert1 aAnneliese Schneider1 aMarina Bacac1 aMichael Bscheider1 aNadine Stokar-Regenscheit1 aSalvatore Piscuoglio1 aJoep Beumer1 aNikolche Gjorevski00aAnalysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids  uhttps://www.nature.com/articles/s41551-023-01156-5  a345-3600 v83 aPredicting 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.  a2157-846X