JAX DOSING STUDIES
Measuring treatment response in Patient Derived Xenograft (PDX) models at The Jackson Laboratory
How are cohorts of tumor bearing mice established for dosing studies?
For cohort expansion donor mice are created using viable, cryopreserved low-passage tumor fragments (P2-P5 unless otherwise noted). With the exception of prostate tumors, all tumors are implanted in female NSG™ mice. Mice are between 6-8 weeks of age at the time of implantation. Tumors are typically implanted subcutaneously into the right flank using a trocar. Breast cancer tumors are sometimes implanted in the mouse mammary fat pad. Implantation site is subcutaneous unless otherwise noted.
Tumors used to establish donor mice are subjected to standard Quality Control procedures to ensure tissue provenance and to validate key tumor markers.
Tumor bearing mice are grouped in cohorts of 8-10 mice using single or rolling enrollment for dosing studies. Mice with tumor sizes of 70-300 mm3 are randomized between treatment groups. Baseline tumor volumes are established and dosing initiation begins on Day 0 or Day 1.
Typical routes of drug administration are as follows:
- Intravenous (IV)
- Intraperitoneal (IP)
- Oral gavage (PO)
- Subcutaneous (SC)
What is the protocol for dosing and measuring drug response in PDX models?
Once tumors become palpable, tumor volumes are measured up to 3X a week with digital calipers. Mice are monitored until their individual tumor volume reaches the approved protocol volume limit.
The in vivo response to treatment is assessed using the percentage of tumor volume change (ΔVol) at the final study day (i.e., seven days after the last treatment) compared with the baseline tumor volume at Day 0 or Day 1. The criteria for response classification classification is based on the combination of the best response and average response (see below) adapted from Gao et al., 2015 .
- Step 1: Calculate percent change in tumor volume for each animal as V: ((end_volume – start_volume)/start_volume) * 100)
- Step 2: Within each group find the minimum V as Vm
- Step 3: Within each group find the mean (average) V as Va
- Step 4: Determine RECIST category as shown in the table below
RECIST Category Best Response: Vm Average Response: Va
Complete Response (CR) < -95% < -40% Partial Response (PR < -50% <-20% Stable Disease (SD) < 35% < 30% Progressive Disease (PD) Anything else
How is animal welfare monitored during dosing studies?
Body weight and clinical observations, including body condition score, grooming and tumor integrity are monitored up to 3X a week for the study duration. Additionally, daily cage side observations are conducted to monitor animal welfare. Veterinary staff is contacted if animals show any signs of distress and veterinary recommendations are followed.
What is the procedure for measuring tumor volume?
Tumor volume measurements are taken up to 3X weekly throughout the duration of each study to assess tumor response to therapy. It is possible for tumor responses to initially exhibit regression (shrinkage) in response to therapy and then resume progressive growth, therefore tumors must be continually monitored throughout the study or risk missing this response. Tumor volumes are calculated from digital caliper raw data by using the formula:
Volume (mm3) = (l x w2) / 2
The value w (width) is the smaller of two perpendicular tumor axes and the value l (length) is the larger of two perpendicular axes. Mean tumor volume growth curves and means are calculated for each treatment group.
More information can be found here .