Revolutionizing CAR T-Cell Therapies: Innovations in Genetic Engineering and Manufacturing to Enhance Efficacy and Accessibility

Abstract

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.

Keywords: ATMP manufacturing; CAR T; GMP-in-a-box; gene editing; hospital exemption.

Figure 1

“Demonstrator CAR” is a fictional testbed incorporating all innovations regarding the construct presented in this article.

Figure 2

The factors that result in the cost of ATMPs today. Quality oversight is reported on top because it encompasses all other aspects of setting up and running a traditional cleanroom operation.

Figure 3

Current limitations and potential benefits of closed systems in ATMP production when compared to open systems adopted by authorized products.

Figure 4

The most useful features of future closed-system devices for expediting production, reducing downtime, and increasing manufacturing quality.