Simultaneous evaluation of treatment efficacy and toxicity for bispecific T‐cell engager therapeutics in a humanized mouse model

Abstract

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of severe adverse events, including cytokine release syndrome (CRS).Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T-cell engager (BiTE). Using this model, we evaluated tumor burden, T-cell activation, and cytokine release in response to bispecific T-cell-engaging antibody in humanized mice generated with different PBMC donors. The results show that PBMC engrafted NOD-scid Il2rg null mice lacking expression of mouse MHC class I and II (NSG-MHC-DKO mice) and implanted with a tumor xenograft predict both efficacy for tumor

Immune‐related adverse events of antibody‐based biological medicines in cancer therapy

“… 171 , 172 Recent developments coupling tumour engraftment in humanized mice have paved way for improved next‐generation in vivo model systems to support our understanding of immune‐oncological responses that maybe encountered in patients following administration of biological therapies. 173 , 174 , 175 Autologous tumour engraftment models combine generation of cancer cell lines by transformation of primary fibroblast or induced pluripotent stem cell (iPSC)‐derived cells in conjunction with human foetal liver CD34 + and autologous foetal thymus tissue engraftment into immunocompromised SCID mice, generating a model referred to as BM, liver, thymus (Hu‐BLT) or humanized mice bearing autologous tumours (Hu‐AT) models. 176 , 177 Patient‐derived xenograft (PDX) models involving the use of patient‐derived tissues/explants simulate several patient‐specific oncological characteristics inclusive of heterogeneity and could likely develop as personalized therapy.…”

“…Several aspects including the ability to adequately represent relevant immune cell subsets such as innate lymphoid cells and neutrophils and model complexities of physiological responses in patients, however, need careful consideration while selecting the model for immuno‐oncological testing 171,172 . Recent developments coupling tumour engraftment in humanized mice have paved way for improved next‐generation in vivo model systems to support our understanding of immune‐oncological responses that maybe encountered in patients following administration of biological therapies 173–175 . Autologous tumour engraftment models combine generation of cancer cell lines by transformation of primary fibroblast or induced pluripotent stem cell (iPSC)‐derived cells in conjunction with human foetal liver CD34 + and autologous foetal thymus tissue engraftment into immunocompromised SCID mice, generating a model referred to as BM, liver, thymus (Hu‐BLT) or humanized mice bearing autologous tumours (Hu‐AT) models 176,177 .…”