Abstract
Cancer immunotherapy is a rapidly growing field in the treatment of cancer and holds great promise for improving patient outcomes. One of the major challenges in the development of T-cell engagers, a type of immunotherapy that redirects T-cells to attack cancer cells drugs, is the risk of on-target/off-tumor toxicity. This occurs when the immune system mistakenly attacks healthy tissues due to expression of target antigen on healthy tissues as well as tumor, leading to severe side effects, including tissue injury and cytokine release syndrome.
In this study, we aimed to extrapolate on-target/off-tumor toxicity by T-cell engager from cynomolgus monkeys to humans, using cyno- and human-derived organoids. For the in vitro assessment, we employed a co-culture system of peripheral blood mononuclear cells (PBMCs) and organoids, which are three-dimensional cell cultures that mimic the structure and target expression of organs. The in vitro data reflected intestinal toxicity observed in in vivo toxicity study with cynomolgus monkeys. Comparing the in vitro result using cyno- and human-derived organoids, we discussed the extrapolation from the preclinical data in cynomolgus monkeys to humans.
This tool helps researchers to better understand the mechanisms of on-target/off-tumor toxicity and extrapolate the results of animal studies to human prediction, thus can be a valuable approach for the safety assessment of T-cell engagers.
