The journey to an innovative therapy: CAR-T cells
T cells equipped with a Chimeric Antigen Receptor, known as CAR-T cells, have had an extraordinary impact on the oncology field. Famously recognized in clinical, scientific, and mainstream circles, CAR-T cells have ushered in a new era in the treatment of advanced, relapsed/refractory blood cancers. Many patients, who were enduring the painful realization that they might lose their fight with cancer after conventional methods of cancer treatment had failed, experienced life-restoring transformation upon receiving an infusion of their own CAR-T cells. Over a decade into many CAR-T treatments, we see reports of decade-long sustained remissions which suggest potential cures for diseases that had long been deemed incurable.
At the heart of CAR-T cell therapy is an elegantly simple premise: we can harness the intrinsic power of immune cells and equip them with the necessary tools to unleash a destructive force capable of eradicating certain forms of cancer. Despite the appearance of simplicity, the most common method of creating a CAR-T cell involves a complex, extensive, and costly manufacturing process that starts with the extraction of the patient’s own T cells. This poses the first challenge. Patients with advanced, metastatic cancers have often received multiple lines of therapy prior to CAR-T, and, as a result, are rendered immunocompromised, possessing fewer T cells that are weaker in function. Taking these cells through the required genetic editing steps and rapid expansion phase constitutes a new set of challenges. Not all manufactures succeed, and thus, not all patients, unfortunately, receive their therapy.
In 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 world. Leveraging strong science, compelling clinical data, and unwavering determination, CAR-T cell pioneers forged a path through regulatory approval, and cleared the way for CAR-T cell therapy to enter the market. The year 2017 marked the arrival of Kymriah and 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 opportunities
Despite 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 CARNK (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 CARmodified 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-ofidentity controls, and establishing standardized, commerciallycompliant 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.
