Prediction of First-in-Human Dose of Chimeric Antigen Receptor-T (CAR-T) Cells from Mice

Area of Science:

• Pharmacology and Toxicology
• Biotechnology
• Cell Therapy

Background:

• No established methods exist for predicting the first-in-human (FIH) dose of chimeric antigen receptor-T (CAR-T) cells.
• Accurate FIH dose prediction is essential for the safe and effective clinical translation of CAR-T cell therapies.

Purpose of the Study:

• To evaluate and identify reliable methods for predicting the FIH dose of CAR-T cells based on preclinical mouse data.
• To compare the predictive accuracy of various scaling methods against established human doses.

Main Methods:

• Six scaling methods were assessed, including body weight-based exponents, human equivalent dose (HED) calculations, modified HED approaches (total animal dose, body surface area), and a physiological factor.
• FIH doses for six CAR-T cell products were predicted using these methods.
• Predicted human doses were validated against US-FDA recommended doses and literature data.

Main Results:

• Two modified HED methods and the physiological factor emerged as the most accurate and reliable approaches for predicting CAR-T cell FIH doses.
• These methods demonstrated superior performance compared to traditional scaling techniques.

Conclusions:

• The identified modified HED methods and physiological factor offer simple, accurate, and spreadsheet-compatible tools for CAR-T cell FIH dose prediction.
• These validated methods can aid in the preclinical to clinical translation of CAR-T cell therapies.