Scientists leveraged donor-matched intestinal organoids of healthy tissues and tumoroids of cancerous tissue, along with immune cells, to capture and scrutinize the inflammatory-like toxicities T-cell-engaging bispecific antibodies (TCBs) may induce. This innovative approach is poised to accelerate the development of safer and efficacious drugs for cancer patients.
In a recent publication in the journal Nature Biomedical Engineering, scientists introduced an innovative human model for earlier and better preclinical prediction of adverse effects from cancer immunotherapies on healthy tissues, termed on-target, off-tumor toxicity. The study was a multi-institutional collaboration spearheaded by first author and PhD student Marius F. Harter and included experts at Roche’s Institute of Human Biology (IHB), Roche Pharma Research and Early Development (pRED) and University of Basel. The collaborators leveraged donor-matched intestinal organoids of healthy tissues and tumoroids of cancerous tissue, along with immune cells, to capture and scrutinize the inflammatory-like toxicities T-cell-engaging bispecific antibodies (TCBs) may induce. This innovative approach is poised to accelerate the development of safer and efficacious drugs for cancer patients.
Cancer immunotherapies, which use immune T cells to target tumours, have been transformative in treating various cancers, but the challenge of preclinical prediction of immunotherapy toxicities on tissue remains significant. Traditional animal models can fall short in fully representing the expression of human antigens and histological features in both tumors and healthy organs. On top, traditional models often cannot fully simulate the human immune response.
The team’s innovative method to address these hurdles involves using patient-derived intestinal organoids to more accurately reflect tissue and antigen features. The authors co-cultured the organoids with peripheral blood mononuclear cells (PBMCs), which also include T cells – the primary responders to the therapies of interest. This method successfully replicated observed clinical toxicities not predicted by conventional preclinical toxicology models and has highlighted variability among patient responses to TCBs.
The study’s potential for translational impact is significant, but it also sheds light on fundamental observations of mechanisms of T-cell-mediated damage to healthy epithelia. The team found that TCB treatment is associated with and likely mediated by lymphocytic infiltration of the epithelium. Strikingly, tumor organoids exhibited more resistance to damage, likely due to a reduced efficiency of T-cell infiltration within the epithelium, pointing to potential epithelium-specific mechanisms of immune evasion by tumor cells that are not yet fully understood. Shedding light on these mechanisms could help researchers find ways to enhance targeting of tumors and mitigate damage of healthy tissue. These results demonstrate the use of patient-derived intestinal organoids as a versatile and patient-relevant model for the preclinical safety and efficacy testing of immunotherapies. This model both aids in understanding the fundamental mechanisms of immune-triggered epithelial killing as well as also guides the development and optimization of immuno-oncology drugs for clinical application.
“This was an exciting project for me because we were not only able to merge two contrasting fields – one of which has only fairly recently emerged, organoid research, whereas histology has been around for centuries – but also to combine both bioengineering and advanced multicolor imaging. The work opened novel avenues to assess our immune-organoid co-cultures in the context of preclinical safety and efficacy assessment of T cell bispecifics at single cell level, uncovering differential immune cell infiltration and killing behavior in the context of healthy and cancerous epithelium.”
Marius Harter
PhD Student
Representative image of tumoroids surrounded by immune cells 72h post T cell bispecific (TCB) treatment. Specifically, the 7plex mIF image highlights EpCAM-TCB triggered killing of the tumoroids (Caspase-3+, green) by activation of cytotoxic CD4+ (orange) and CD8+ (cyan) T cells infiltrating and lysing the epithelium of the tumoroid (Caspase-3+, panCK+, magenta), with B cells (CD20+, yellow) and myeloids cells (CD14+, red) around, nuclei are stained with DAPI (blue). Multicolor immunofluorescence = mIF. Credit: Marius Harter.
Harter MF, Recaldin T, Gerard R, Avignon B, Bollen Y, Esposito C, Guja-Jarosz K, Kromer K, Filip A, Aubert J, Schneider A, Bacac M, Bscheider M, Stokar-Regenscheit N, Piscuoglio S, Beumer J, Gjorevski N. Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids. Nat Biomed Eng. 2023. DOI: 10.1038/s41551-023-01156-5
Read the full paper: https://rdcu.be/dz85n