Optimization of CAR T-cell dose: a debated unresolved issue

CAR T-cell therapies are incredibly potent in killing tumour cells and have been extremely successful in putting hematologic patients into remission. However, there are still multiple challenges such as life-threatening toxicities and high relapse rates. Balancing the anti-tumor efficacy while sparing detrimental toxicities would be the desirable outcome. CAR T-cells behave as “living multi-drugs” because each cell type has its own kinetic and dynamic parameters. Therefore, the kinetics and function of a CAR T-cell product is unpredictable and variable. Optimising the CAR T-cell dose in terms of cell numbers and subpopulations, is extremely challenging as multiple factors seem to have an impact on CAR T-cell function, while published clinical trials have used a wide range of cell doses rendering the comparison of outcomes elusive. We propose a research model for determining the optimal therapeutic dose in CAR T-cell personalized therapies. We believe that both toxicity and relapse do not seem to be with the cellular products, per se, but rather with the followed therapeutic strategy. Scientists should turn backwards 180° degrees and take the reverse research direction to find the underlying root causes. The disconnection of the CAR-T product efficacy from long-term persistence is set as a prerequisite. Developing a model that identifies root causes of adverse events could lead to personalized therapies with optimized dosing and reduced side effects. Such advancements could facilitate outpatient treatment administration, reduce healthcare costs, and increase patient access to CAR T-cell therapies.