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

Authors

Jiwon YangFollow
Jing Jiao, The Jackson Laboratory
Kyle Draheim, The Jackson LaboratoryFollow
Guoxiang Yang, The Jackson LaboratoryFollow
Hongyuan Yang, The Jackson LaboratoryFollow
Li-Chin Yao, The Jackson LaboratoryFollow
Leonard D. Shultz, The Jackson LaboratoryFollow
Dale L Greiner
Deepa Rajagopal
Sandrine Vessillier
Curtis C Maier
Sunish Mohanan
Danying Cai, The Jackson LaboratoryFollow
Mingshan Cheng, The Jackson LaboratoryFollow
Michael A Brehm
James G. Keck, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

6-1-2023

Original Citation

Yang J, Jiao J, Draheim K, Yang G, Yang H, Yao L, Shultz LD, Greiner D, Rajagopal D, Vessillier S, Maier C, Mohanan S, Cai D, Cheng M, Brehm M, Keck JG. Simultaneous evaluation of treatment efficacy and toxicity for bispecific T-cell engager therapeutics in a humanized mouse model. Faseb j. 2023;37(6):e22995

Keywords

JCA, JMG, Humans, Animals, Mice, Mice, Inbred NOD, Leukocytes, Mononuclear, T-Lymphocytes, Treatment Outcome, Cytokine Release Syndrome, Cytokines, Disease Models, Animal, Mice, Knockout, Mice, SCID

JAX Source

Faseb j. 2023;37(6):e22995

ISSN

1530-6860

PMID

37219526

DOI

https://doi.org/10.1096/fj.202300040R

Abstract

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treat- ment of several cancer indications. However, these therapies can result in the de- velopment 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 Il2rgnull 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 control by CD19xCD3 BiTE and stimulated cytokine release. Moreover, our find- ings indicate that this PBMC-engrafted model captures variability among donors for tumor control and cytokine release following treatment. Tumor control and cytokine release were reproducible for the same PBMC donor in separate experi- ments. The PBMC humanized mouse model described here is a sensitive and re- producible platform that identifies specific patient/cancer/therapy combinations for treatment efficacy and development of complications.

Comments

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.