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 a 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% of 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 the 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 113 studies with in vivo components, immuno- competent animal models were used in 24.8%. Measurements 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% of studies. The surface expression level of CAR, functional characterization of the product, and use of control were reported in >90% of studies. CONCLUSION: The 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.