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.

Preparing for the future of precision medicine: synthetic cell drug regulation

“…For CAR-T cells, the FDA also recommends that drug developers account for all risks associated with cellular starting materials for these cell therapies ( 18 ). Here begins a major gap in regulatory guidelines for synthetic cells, as they will be the first of their kind to not originate from cellular starting materials.…”

Outpatient CAR T-Cell Therapy as Standard of Care: Current Perspectives and Considerations

“…Per the European Medicines Agency, CAR-T therapy falls under the designation of Advanced Therapy Medicinal Products (ATMP). 37 In the European Union (EU), decision-making related to pricing and reimbursement is done at a national level and each country must make its own health technology assessment regarding effectiveness, safety, medical necessity, cost-effectiveness and budget impact. 37 Outcome-based reimbursement and spread payment models are being increasingly used in the EU for CAR-T to help increase affordability.…”

Modern immunotherapy using CAR-T cells in haemato-oncology and solid tumors

“…The modified lymphocytes are multiplied to a quantity capable of fighting the cancer and then sent back to the clinic where the patient is waiting for them. The last stage of therapy consists of administering CAR-T cells to the patient by infusion [6,7]. But like any other therapy, CAR-T cell therapy can cause side effects.…”

“…Some patients may experience cytokine release syndrome or neurotoxicity during the first days of treatment. The growing clinical experience of treatment with CAR-T immunotherapy means that clinicians are developing a growing understanding of how to eliminate these complications [6].…”

“…As of April 2023, there were six United States (US) Food and Drug Administration (FDA)--approved CAR-T cell products: Kymriah™ (tisagenlecleucel), Yescarta™ (axicabtagene ciloleucel), Tecartus™ (brexucabtagene autoleucel), Breyanzi ® (lisocabtagene maraleucel), Abecma™ (idecabtagene vicleucel), and Carvykti™ (ciltacabtagene autoleucel). Thanks to this clinical success, CAR-T cell therapy has become one of the most promising Anna Bogacz et al, CAR-T cell therapy in haemato-oncology and solid tumors second-generation chimeric CAR receptor [2,5,6]. There are at least four generations of CAR-T cells.…”