Quality Assessment of Pre-Clinical Studies of Chimeric Antigen Receptor T-Cell Therapy Products: A Point of Focus On Safety.

Background Serious adverse reactions have been reported with the use of chimeric antigen receptor (CAR) T-cell therapy in clinical setting despite the success of these products in pre-clinical stages of development. Objective We evaluated the quality of available pre-clinical safety data of CAR T-cell therapy products. Methods A 21 items safety-checklist was designed specifically for CAR T-cell. Literature was searched using search/MeSH terms in PubMed (October 2019 - February 2020). Studies were screened from title and abstract. Original pre-clinical researches related to CAR T-cell anti-cancer therapy were included. Results Of the search results, 152 studies (3 in vivo, 39 in vitro, and 110 combined) were included. Only 7.9% studies were specifically designed to evaluate/ improve product safety. Eleven studies included target antigen(s) and no study included co-stimulatory molecule(s) expressed exclusively by tumor tissue and/or CAR T-cells. One study used CRISPR-Cas9 for CAR gene insertion. The use of switch-off mechanism and purity assessment of CAR T-cell products were reported in 13.2% and 8.6% studies respectively. Of the 149 studies with in vivo component, immuno-competent animal models were used in 24.8%. Measurement of blood pressure, temperature, body weight and serum cytokines were reported in 0, 2.7, 29.2 and 27.4% studies respectively. The tissue distribution and CAR T-cells persistence were reported in 26.5% studies. Conclusion Majority of the checklist parameters were not reported in the pre-clinical publications to be adequately predictive of the safety of CAR T-cells in a clinical setting.