# The Future of Off-the-Shelf CAR-T Therapies: A New Era in Treatment
Written on
Chapter 1: Introduction to CAR-T Therapies
In late 2017, the U.S. FDA granted approval for the initial two CAR-T cell therapies: Novartis’ Kymriah, aimed at treating acute lymphoblastic leukemia (ALL), and Gilead’s Kite Pharmaceutical’s Yescarta, designated for specific forms of large B-cell lymphomas—part of the non-Hodgkin lymphoma category. These therapies are classified as autologous, meaning they are tailored to individual patients. The process involves extracting the patient’s T-cells (a type of white blood cell) from their bloodstream, preserving them, and sending them to a facility for genetic modification. This process enables the T-cells to identify and combat the patient’s unique cancer cells by altering their receptors, resulting in the creation of chimeric antigen receptor T-cells (CAR-T cells) that are then infused back into the patient.
While this groundbreaking approach is transforming cancer care, it does come with significant drawbacks.
Section 1.1: Challenges with Current Autologous CAR-T Therapies
Due to their personalized nature, these therapies can only be used on the patient from whom the T-cells were derived. If Patient B were to receive Patient A’s CAR-T cells, they would attack all of Patient B’s cells, mistaking them for foreign invaders. Furthermore, the process is labor-intensive and typically requires 3 to 4 weeks for production, which can be critical for patients in need of rapid intervention. In contrast, many non-personalized therapies can be administered almost immediately.
The intricate manufacturing process also significantly increases costs, with Kymriah priced at $475,000 and Yescarta at $373,000.
This video titled "CAR-T Cell Therapy: Current Uses and Future Possibilities" provides insights into the current applications of CAR-T therapies and explores potential advancements in this field.
Section 1.2: Advancements Toward Off-the-Shelf CAR-T Therapies
To address these challenges, researchers are now focusing on the next wave of CAR-T therapies: allogeneic or “off-the-shelf” treatments that can be mass-produced from healthy donor cells, allowing for broader patient access.
At the University of California, Los Angeles (UCLA), scientists have successfully transformed pluripotent stem cells into T-cells using artificial thymic organoids. These organoids are simplified, three-dimensional models that emulate the thymus, where T-cells naturally develop from blood stem cells. In research published in Cell Stem Cell, they demonstrated that these organoids facilitate effective T-cell maturation. They successfully generated mature T-cells from both human embryonic stem cells and induced pluripotent stem cells (iPSCs), which are reprogrammed from adult tissue.
Gay Crooks, a senior author of the study, expressed excitement about the potential of combining this technique with gene editing tools to create readily available "off-the-shelf" T-cell therapies for patients.
Subsection 1.2.1: The Promise of Artificial Thymic Organoids
Researchers have shown that T-cells produced in this manner can be genetically modified to target and eliminate tumors in mouse models. The goal is to develop stem cell lines capable of producing tumor-specific T-cells that can be expanded indefinitely.
However, this innovative technology still faces hurdles. T-cells derived from artificial thymic organoids may express surface proteins that could lead to rejection by patients. The next phase of research aims to develop T-cells that retain their cancer-fighting capabilities but lack the rejection markers.
Chapter 2: The Biopharmaceutical Landscape of Off-the-Shelf Therapies
The video titled "What is the Future of CAR-T Cell Therapy - Science of Healing CLIP" delves into what lies ahead for CAR-T therapies and the transformative potential of off-the-shelf options.
Off-the-shelf therapies have become a significant focus in the biopharmaceutical sector, with numerous companies pursuing breakthroughs in this area, including the UCLA/Kite collaboration. Cellectis is leading the charge in gene editing, utilizing TALEN technology to develop allogeneic CAR-T therapies, also known as Universal CAR-T cells (UCARTs). They are advancing several UCARTs, with trials underway for various types of leukemia and lymphoma.
Collaborating with Allogene Therapeutics, Cellectis is developing therapies like ALLO-501, aimed at CD19-positive relapsed or refractory non-Hodgkin lymphoma. The FDA has given investigational new drug (IND) status to ALLO-501, and a Phase 1 trial is anticipated soon.
The ongoing trials have shown promising outcomes, including a notable response rate in patients receiving combination therapies. Despite the relative infancy of allogeneic CAR-T technology, there is great potential for efficiency in manufacturing, with estimates suggesting that one batch could treat up to 100 patients.
In conclusion, as research continues to advance, the future of CAR-T therapies looks promising, particularly with the development of off-the-shelf options that aim to make these life-saving treatments more accessible and affordable for patients in need.