For more than a decade, chimeric antigen receptor T-cell (CAR T) therapy has transformed the treatment landscape for certain blood cancers. Now, researchers believe the next major leap might come from combining CAR T with powerful gene-editing technologies such as CRISPR (which stands for clustered regularly interspaced short palindromic repeats) and TALEN (which stands for transcription activator-like effector nucleases), opening new possibilities for rare diseases that have long lacked effective treatment options.
A leading example of this approach comes from CRISPR Therapeutics, which is developing next-generation gene-edited CAR T-cell therapies designed to be available off the shelf rather than custom-made for each patient. By using CRISPR-Cas9 to make multiple precise genetic modifications, the company aims to create more potent, durable, and scalable cancer treatments while reducing the manufacturing challenges associated with traditional autologous CAR T therapies
Although CAR T cells are designed to recognize and destroy specific disease-causing cells, gene editing allows scientists to enhance the CAR T cells with additional capabilities, improving their performance, safety, and durability
“The benefit is huge,” said Philippe Duchateau, PhD, CSO at Cellectis. “By using gene editing … you can bring new properties to these T cells on top of the CAR.”
Researchers increasingly view gene editing not as a simple add-on but as a foundational technology that can help overcome many of CAR T’s current limitations. According to Cesar Sommer, PhD, vice president of research at Allogene Therapeutics, gene editing allows developers to design cell therapies with greater precision from the outset
Moreover, “CRISPR adds an important layer of precision to CAR T engineering by enabling targeted edits that can improve T cell function, resistance to exhaustion, and safety,” Sommer explained
Beyond oncology
Recent studies have demonstrated the potential of CAR T therapies targeting B cells and plasma cells in conditions such as systemic lupus erythematosus, myasthenia gravis, and stiff-person syndrome. In these diseases, malfunctioning immune cells produce harmful autoantibodies that attack healthy tissues
Scientists are also investigating engineered T cells for rare fibrotic disorders. Duchateau pointed to fibrosis as an intriguing target, suggesting that CAR T cells could be programmed to recognize and eliminate the cells driving tissue scarring in organs such as the liver or heart
“You can engineer a T cell, for example, that will recognize a specific antigen linked to the fibrosis,” Duchateau said. “It will go there and destroy this fibrotic area.”
TALEN versus CRISPR
Although CRISPR has become synonymous with gene editing, TALEN technology continues to play an important role in cell-therapy development. Cellectis primarily relies on its proprietary TALEN platform to engineer allogeneic CAR T products. According to Duchateau, TALEN and CRISPR achieve similar levels of editing efficiency, but “the superiority of TALEN is within the specificity,” he said. TALEN recognizes a longer DNA target sequence and requires two separate molecules to bind at the correct position before a DNA cut occurs, creating an additional safeguard against unintended edits.
CRISPR, meanwhile, remains attractive because of its relative simplicity and accessibility. Researchers can rapidly design CRISPR-based experiments, making it a powerful discovery tool and a key driver of innovation in the field.
Rather than viewing the technologies as competitors, many researchers see them as complementary. Duchateau noted that future therapies might combine multiple editing approaches, including base editing and epigenetic modifications, to maximize safety and functionality
The rise of off-the-shelf CAR T
Traditional autologous CAR T therapies require T cells to be collected from an individual patient, modified, and reinfused weeks later. This process can be expensive, time-consuming, and vulnerable to manufacturing failures, particularly when patients are heavily pretreated
Alternatively, allogeneic CAR T therapies use healthy donor cells that are edited and manufactured in advance. Gene editing eliminates components like the native T cell receptor, reducing the risk of graft-versus-host disease and enabling broader patient compatibility
“When a patient comes to the clinic, the cells are available right away,” Duchateau said.
Sommer believes these targeted edits could help address many of the access and manufacturing challenges that have limited the broader adoption of CAR T therapies. Standardized products might be particularly valuable for rare diseases, for which patient populations are small and individualized manufacturing can be difficult
Adding precision and durability
The combination of CRISPR gene editing and CAR T-cell therapy is emerging as one of the most promising strategies for developing next-generation cellular medicines. According to Emily Leproust, PhD, CEO and co-founder of Twist Bioscience, the technology pairing allows researchers to engineer immune cells with greater precision, potency, and durability than earlier generations of CAR T therapies
Twist Bioscience supports this work through a suite of synthetic biology tools designed to accelerate target discovery and cell engineering. Researchers can use Twist Cloned Oligo Pools to create single- and dual-guide RNA libraries for CRISPR screening, enabling systematic evaluation of genes that might serve as therapeutic targets. Once validated, those targets can be incorporated into the design of improved CAR T therapies
Leproust highlighted three major applications driving the field forward. The first is the development of universal, off-the-shelf CAR T therapies through multiplex gene editing. By knocking out genes such as TRAC, HLA, and CD52, scientists can convert donor-derived T cells into allogeneic products that can be administered to multiple patients. “This is the basis of allogeneic products, and of base-edited therapies already used in children with relapsed leukemia,” she said
A second strategy involves removing molecular “brakes” on T cell activity. Eliminating inhibitory genes such as PDCD1 can enhance both persistence and antitumor activity. The third approach inserts CAR constructs into specific genomic locations, such as the TRAC locus, instead of relying on semi-random viral integration. According to Leproust, this results in “uniform physiologic expression, fitter cells, and avoids the insertional-mutagenesis risk of semi-random integration.”
Twist’s extensive T-cell receptor (TCR) and CAR libraries further support innovation by allowing researchers to simultaneously test large numbers of receptor combinations. Combined with artificial intelligence (AI)-driven screening, these capabilities are helping scientists identify stronger therapeutic candidates while expanding the range of diseases that engineered cell therapies might eventually treat
Scaling from research to the clinic
As CAR T therapies become increasingly sophisticated through CRISPR-based engineering, manufacturing, and process development have become just as important as the underlying biology. Namritha Ravinder, PhD, director of cell and gene therapy R&D at Thermo Fisher Scientific, emphasizes that successful development requires coordination across every stage of the workflow, from cell isolation and gene editing to expansion, analytical testing, and commercial-scale production
Thermo Fisher provides technologies and services that support these crucial steps, like its Gibco CTS portfolio of good manufacturing practices (GMP)-compatible reagents and a range of platforms. Among the key tools are the TrueCut™ HiFi Cas9 Protein, designed for high-fidelity genome editing, and the LV-MAX™ Lentiviral Production System, which supports manufacturing of high-titer lentiviral vectors for cell therapy applications
“Our portfolio of closed, automated, and modular manufacturing solutions supports key cell therapy manufacturing steps, from cell isolation and gene delivery to cell processing, expansion, formulation, and final fill-finish,” Ravinder explained. These systems are intended to reduce manufacturing complexity while improving consistency and scalability
The importance of these capabilities becomes even more pronounced in rare disease applications, where small patient populations and limited development reRavinder noted that combining CRISPR and CAR T technologies enables the creation of therapies with “greater precision and therapeutic potential,” while streamlined manufacturing workflows can help accelerate their path to the clinic
A key advantage of Thermo Fisher’s approach is continuity between research and clinical manufacturing. Developers can often transition from research-use products to comparable manufacturing-grade reagents, reducing process changes as programs advance through development
Beyond products, Thermo Fisher’s Advanced Therapies Collaboration Center provides process optimization and workflow development expertise. By integrating manufacturing technologies with development support, the company aims to help therapy developers transform promising laboratory discoveries into scalable clinical products. As CRISPR-enhanced CAR T therapies move toward broader clinical adoption, such manufacturing innovations will be essential to bringing advanced cell therapies to patients with rare diseases and other areas of significant unmet medical need.
A new generation of cell therapies
Beyond individual gene modifications, CRISPR is increasingly being used in large-scale screening programs to identify genetic changes that improve CAR T performance. Researchers can simultaneously evaluate thousands of potential targets and discover edits that enhance cell expansion, persistence, and resistance to immune suppression
“These insights can then be translated into next-generation engineered cell therapies that are more robust and more effective,” Sommer said
As CAR T technology converges with increasingly sophisticated gene-editing platforms, the result could be a new class of programmable cell therapies capable of tackling diseases far beyond cancer. For patients with rare autoimmune, fibrotic, and genetic disorders, that convergence might ultimately offer treatment options where few currently exist
The emerging vision is not simply better CAR T therapy. It is a future in which engineered immune cells can be customized with unprecedented precision, creating safer, more durable, and more accessible treatments for some of medicine’s most challenging rare diseases
Mike May, PhD, is a freelance writer and editor with more than 30 years of experience. He earned an MS in biological engineering from the University of Connecticut and a PhDin neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of more than 1,000 articles for clients that include GEN, Nature, Science, Scientific American, and many others. In addition, he served as the editorial director of many publications, including several Nature Outlooks and Scientific American Worldview.
News & FeaturesCell therapyCRISPRGood manufacturing practiceGraft versus host diseaseRare diseasesT-cell immunotherapy
