| | AUGUST 20249CIOReviewIn a relatively short amount of time, clinicians and scientists have advanced the concept of transforming one's own immune cells into potent anti-cancer agents and moved rapidly toward bringing these innovative therapies to hospitals around the worldand Yescarta - the first commercial CAR-T products targeting advanced lymphoma and acute lymphoblastic leukemia. Building on what was learned from these successes, the next five years brought forth four new CAR-T therapies, further expanding the arsenal of cell-based treatments against cancer. Challenges and new opportunitiesDespite the unprecedented successes seen in the CAR-T journey and the accelerated pace at which the field has advanced in this past decade, many challenges still remain. CAR-T cells have not yet shown the same efficacy in solid tumors as seen for blood cancers. This may be largely due to the inherently complex nature of the solid tumor microenvironment, where an abundance of suppressive signals and diminished oxygenation weaken the immune response. Aware of these obstacles, the field turned to new strategies, seeking to leverage tumor-fighting capabilities of other cells of the immune system. Soon, CAR-T cells were joined by CAR-NK (natural killer cells), CAR-NKT (natural killer T cells), and CAR-M (macrophages). Moreover, supported by advancements in single-cell multiomics, insights into the genetics and epigenetics of tumor and immune cells have helped to elucidate new functionalities that can be further engineered into CAR-modified cell therapies. Bringing novel therapies to patients faster Today, a growing number of next-generation products are advancing through the pre-clinical and clinical development phases. To broaden patient access to these potentially curative treatments, some of these products are built on allogeneic cell sources, in order to establish off-the-shelf cell therapies that are readily available to many patients. Devising a viable strategy to ensure timely and efficient manufacturing of these cell-based drugs is a critical step to ensure patients receive their treatment as quickly as possible. Despite the notable progress in therapy development, manufacturing still remains a bottleneck that delays the transition of these drugs to the clinic. Because cell-based therapies, unlike other medicines, are "living drugs" whose properties can be altered by even small manipulations and process changes, it is also important to design an appropriate manufacturing strategy to support robust and reproducible generation of the clinical product. Integration of automation into the manufacturing process can reduce costs and labor by consolidating multiple unit operations into a single platform, supporting large-scale production, and reducing errors. Given the fast-growing product pipeline, developing flexible and scalable platforms that support large-scale manufacturing of both autologous and allogeneic products is necessary to enable a viable path to commercial readiness.Moreover, defining whether manufacturing will be governed by a distributed or a centralized model will play an important role in identifying strategies that best suit each product and clinical intent. Additionally, applying tools such as automated tracking systems, chain-of-custody/chain-of-identity controls, and establishing standardized, commercially-compliant quality assurance programs are critical steps to support robust implementation. Involving regulators early on in this decision-making process can provide guidance and clarity and help to increase the speed of development, enabling innovators to bring these therapies to patients faster.
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