CAR-T State of the Art and Future Challenges, A Regulatory Perspective

Abstract

This review is an outlook on CAR-T development up to the beginning of 2023, with a special focus on the European landscape and its regulatory field, highlighting the main features and limitations affecting this innovative therapy in cancer treatment. We analysed the current state of the art in the EU and set out a showcase of the field's potential advancements in the coming years. For this analysis, the data used came from the available scientific literature as well as from the European Medicines Agency and from clinical trial databases. The latter were investigated to query the studies on CAR-Ts that are active and/or relevant to the review process. As of this writing, CAR-Ts have started to move past the "ceiling" of third-line treatment with positive results in comparison trials with the Standard of Care (SoC). One such example is the trial Zuma-7 (NCT03391466), which resulted in approval of CAR-T products (Yescarta™) for second-line treatment, a crucial achievement for the field which can increase the use of this type of therapy. Despite exciting results in clinical trials, limitations are still many: they regard access, production, duration of response, resistance, safety, overall efficacy, and cost mitigation strategies. Nonetheless, CAR-T constructs are becoming more diverse, and the technology is starting to produce some remarkable results in treating diseases other than cancer.

Keywords: ATMP; CAR-T; EMA; compassionate use; hospital exemption; rare diseases.

Figure 1

From a sample of blood, either from patients or donors, T or NK cells are harvested and transfected with the gene encoding CAR. The resulting CAR-T/-NK cells, bearing the chimeric receptor, are administered to patients. The interaction between CAR-T/-NK cells with tumour cells will lead to lysis.

Figure 2

All possible CAR configurations with depictions of possible domains, their name, and the most relevant parameters influencing their activity. Proteins in rows on the left are potential candidates to fill the role of the list of domains on the right.

Figure 3

Limitations and challenges of CAR-Ts at present are summarised into three main areas. The most significant adverse drug reactions are in red, the factors resulting in resistance to CAR-T activity are in green, and the factors limiting access to CAR-T-cell therapy are in blue.

Figure 4

Steps of the prototypical centralised model, the one adopted by authorised CAR-T products versus a decentralised model, much more compact and less variable.