Armando Magrelli

Chimeric antigen receptor (CAR) T-cell therapy has achieved notable success in treating hematological cancers but faces significant challenges in solid-tumor treatment and overall efficacy. Key limitations include T-cell exhaustion, tumor relapse, immunosuppressive tumor microenvironments (TME), immunogenicity, and antigen heterogeneity. To address these issues, various genetic engineering strategies have been proposed. Approaches such as overexpression of transcription factors or metabolic armoring and dynamic CAR regulation are being explored to improve CAR T-cell function and safety. Other efforts to improve CAR T-cell efficacy in solid tumors include targeting novel antigens or developing alternative strategies to address antigen diversity. Despite the promising preclinical results of these solutions, challenges remain in translating CAR T-cell therapies to the clinic to enable economically viable access to these transformative medicines. The efficiency and scalability of autologous CAR T-cell therapy production are hindered by traditional, manual processes which are costly, time-consuming, and prone to variability and contamination. These high-cost, time-intensive processes have complex quality-control requirements. Recent advancements suggest that smaller, decentralized solutions such as microbioreactors and automated point-of-care systems could improve production efficiency, reduce costs, and shorten manufacturing timelines, especially when coupled with innovative manufacturing methods such as transposons and lipid nanoparticles. Future advancements may include harmonized consumables and AI-enabled technologies, which promise to streamline manufacturing, reduce costs, and enhance production quality.

This manuscript explores significant advancements and emerging challenges in CAR T cell therapies, focusing on the production methodologies and regulatory complexities. The discussion highlights ongoing challenges like the lack of in vivo persistence, lengthy production times, and elevated costs associated with current CAR T cell therapies. It analyzes innovative solutions such as genetic engineering techniques aimed at enhancing cellular efficacy and endurance, alongside cutting-edge manufacturing processes, including closed systems and development of allogeneic products. These advancements hold promise for reducing costs and improving production efficiency, potentially increasing patient access to these transformative therapies globally. Furthermore, the manuscript underscores the necessity for expanding ongoing research and enhancing regulatory frameworks to fully realize and implement these innovations in CAR T cell manufacturing and bring these innovations to fruition.

Inherited Retinal Dystrophies (IRD) are diverse rare diseases that affect the retina and lead to visual impairment or blindness. Research in this field is ongoing, with over 60 EU orphan medicinal products designated in this therapeutic area by the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). Up to now, COMP has used traditional disease terms, like retinitis pigmentosa, for orphan designation regardless of the product's mechanism of action. The COMP reviewed the designation approach for IRDs taking into account all previous Orphan Designations (OD) experience in IRDs, the most relevant up to date scientific literature and input from patients and clinical experts. Following the review, the COMP decided that there should be three options available for orphan designation concerning the condition: i) an amended set of OD groups for therapies that might be used in a broad spectrum of conditions, ii) a gene-specific designation for targeted therapies, and iii) an occasional term for products that do not fit in the above two categories. The change in the approach to orphan designation in IRDs caters for different scenarios to allow an optimum approach for future OD applications including the option of a gene-specific designation. By applying this new approach, the COMP increases the regulatory clarity, efficiency, and predictability for sponsors, aligns EU regulatory tools with the latest scientific and medical developments in the field of IRDs, and ensures that all potentially treatable patients will be included in the scope of an OD.

Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency’s Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.

Adoptive cell therapies exploit the body’s immune system to target and treat oncological conditions. Many substances are developed to treat rare haematological malignancies which fulfil the criteria for being considered as orphan conditions according to the EU Orphan Regulation (1-2). Chimeric antigen receptor (CAR)-T cell products belong to this group of therapy. The Committee for Orphan Medicinal Products has reviewed 23 adoptive cell therapies which were associated with 36 different applications for orphan designation (OD) over a 10-year period, and nineteen of these were CAR-T cell products intended to treat various rare conditions. Most of these products were developed for the treatment of rare haematological malignancies. Preliminary clinical data was used in 80% (29/36) of the OD submissions to support medical plausibility (promise of efficacy) of the candidate products and an assumption of significant benefit, which is the added benefit of the new product over currently authorised medicines for the proposed orphan condition. Eighty-nine percent (32/36) cases of significant benefit were accepted based on a clinically relevant advantage. Twelve of fourteen submissions reviewed for maintenance of the OD at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing therapies within the approved therapeutic indications, but one of these were withdrawn during the evaluation. In conclusion, adoptive cell immunotherapy is a dynamic field in the treatment of haematological malignancies. In the case of applications and ODs granted by the European Commission, autologous CAR-T cell products using a lentiviral vector represent most of the submissions, while CD19 was the most frequently targeted antigen. Clinical data was the most common type of data taken into account at the time of initial OD to support medical plausibility. A high rate of successful initial ODs for these products also seem to translate into a high success rate at the time of marketing authorisation or extension of indication.

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.

Background: Reference to so-called real-world data is more often made in marketing authorization applications for medicines intended to diagnose, prevent or treat rare diseases compared to more common diseases. We provide granularity on the type and aim of any external data on efficacy aspects from both real-world data sources and external trial data as discussed in regulatory submissions of orphan designated medicinal products in the EU. By quantifying the contribution of external data according to various regulatory characteristics, we aimed at identifying specific opportunities for external data in the field of orphan conditions.Methods: Information on external data in regulatory documents covering 72 orphan designations was extracted. Our sample comprised public assessment reports for approved, refused, or withdrawn applications concluded from 2019–2021 at the European Medicines Agency. Products with an active orphan designation at the time of submission were scrutinized regarding the role of external data on efficacy aspects in the context of marketing authorization applications, or on the criterion of “significant benefit” for the confirmation of the orphan designation at the time of licensing. The reports allowed a broad distinction between clinical development, regulatory decision making, and intended post-approval data collection. We defined three categories of external data, administrative data, structured clinical data, and external trial data (from clinical trials not sponsored by the applicant), and noted whether external data concerned the therapeutic context of the disease or the product under review.Results: While reference to external data with respect to efficacy aspects was included in 63% of the approved medicinal products in the field of rare diseases, 37% of marketing authorization applications were exclusively based on the dedicated clinical development plan for the product under review. Purely administrative data did not play any role in our sample of reports, but clinical data collected in a structured manner (from routine care or clinical research) were often used to inform on the trial design. Two additional recurrent themes for the use of external data were the contextualization of results, especially to confirm the orphan designation at the time of licensing, and reassurance of a large difference in treatment effect size or consistency of effects observed in clinical trials and practice. External data on the product under review were restricted to either active substances already belonging to the standard of care even before authorization or to compassionate use schemes. Furthermore, external data were considered pivotal for marketing authorization only exceptionally and only for active substances already in use within the specific therapeutic indication. Applications for the rarest conditions and those without authorized treatment alternatives were especially prominent with respect to the use of external data from real-world data sources both in the pre- and post-approval setting.Conclusion: Specific opportunities for external data in the setting of marketing authorizations in the field of rare diseases were identified. Ongoing initiatives of fostering systematic data collection are promising steps for a more efficient medicinal product development in the field of rare diseases.

Objective: Next-generation sequencing (NGS) technology, changing the diagnostic approach, has become essential in clinical settings, and its adoption by public health laboratories is now the practice. Despite this, as technological innovations, its intake requires an evaluation of both the clinical utility and the economic investment, especially considering the rare disease scenario. This study evaluated the analytical validity and the budget impact of an NGS-Ion Torrent™ approach for the molecular germline diagnosis of two musculoskeletal rare diseases.Methods: Two cohorts of 200 and 199 patients with suspect or clinical diagnosis of multiple osteochondromas (MO) and osteogenesis imperfecta (OI) previously evaluated with a single-gene diagnostic protocol were re-analyzed using a targeted NGS assay. Analytical validity was assessed by comparing NGS and single-gene protocol. A budget impact analysis using real-world cost data-considering the healthcare perspective— was performed by applying activity-based costing (ABC). The cost considered consumables, personnel, and equipment. Additional costs not related to NGS activities were not considered. Sensitivity analysis was performed.Results: The NGS method showed a higher (for MO) and comparable (for OI) diagnostic sensitivity than the traditional techniques, apart from always reducing the time and costs of diagnosis. Overall, the cost saving per patient is € 765 for OI and € 74 for MO. Materials represented the highest cost driver of the NGS process. A time saving—proportional to the panel size—has been assessed in both cases.Conclusions: Our targeted NGS diagnostic approach decreases time to diagnosis and costs, appearing to be beneficial and recommended both for patients and from a healthcare perspective in routine diagnosis also considering very small gene panels and a low patient flow. The adequate analytical sensitivity always required the additional Sanger sequencing step of the low- and non-covered regions. A more accurate strategy evaluation is suggested in the case of ultra-rare/complex diseases, large gene-panel, or non-reference diagnostic centers.