CAR-T cell therapy in NSG mouse model (GLP / non-GLP)



Field of application

The use of CAR-T cell therapy can be associated with significant side effects, which can be divided into three categories: 1) on-target/on-tumor, 2) on-target/off-tumor, and 3) off-target/off-tumor toxicity. Critical on-target/on-tumor side effects include tumor lysis syndrome (Bonifant et al., 2016). In tumor lysis syndrome, the rapid death of many cancer cells results in the abrupt, massive release of intracellular ions, nucleic acids, proteins, and their metabolites into the extracellular space. These metabolites can disrupt the body's normal homeostatic mechanisms, causing uremia, hyperkalemia, hyperphosphatemia, and hypocalcemia, among other symptoms. Tumor lysis syndrome can subsequently lead to acute renal failure (Cairo and Bishop, 2004).

Therefore, it is important to detect and evaluate potential side effects of CAR-T cell therapy in correlation to the therapeutic effect achieved using appropriate in vivo models. For this preclinical testing we use humanized tumor mice that develop tumors by injection of tumor cell lines (CDX - cell line derived) or patient derived (PDX - patient derived) material. In addition to assessing the clinical behavior of the animals, bioluminescence imaging can also be used to assess the effect of the CAR-T cells. After the end of the trial, on-target/off-tumor but also off-target/off-tumor toxicities can be investigated in histological analyses.

Endpoints/outcome parameter

  • Clinical score
  • Analysis of relevant markers in peripheral blood (Hematology/Clinical pathology)
  • Flow cytometric analysis of CAR-T cells and circulating tumor cells in peripheral blood 
  • Bioluminescence imaging of tumor growth
  • Histological/Immunohistochemical analysis of various organs using immune cell and tumor markers

Readout parameter

  • Flow cytometric analysis
  • Bioluminescence imaging
  • Histology/Immunoistochemistry
  • Clinical chemistry

Quality management and validation

  • Internal quality management (certified GLP test facility)
  • Use of reference compounds (Standard-of-care therapies)
  • Randomisation
  • Blinded induction, data acquisition and analysis
  • Biometric expertise