In Vivo CAR T Needs More Than Better Cell Engineering
By Erin Harris, Editor-In-Chief, Cell & Gene
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As the CGT industry looks for ways to make powerful therapies more accessible, in vivo CAR T is one of the approaches generating significant interest. But its success will depend not only on the CAR T construct itself, but on whether the delivery system can safely and efficiently reach the right cells and provide the appropriate duration and level of expression.
Earlier this summer, I launched a special series of Cell & Gene: The Podcast exploring in vivo approaches from the perspective of CGT developers. I encourage you to listen to the first three conversations, which offer valuable insight into where the field is headed. I also spoke with Ying Tam, Ph.D., CSO of Acuitas Therapeutics, to add another very important perspective to the series. His insights focus on the delivery technology needed to turn the promise of in vivo CAR T into a viable therapeutic approach.
Focus on Access as the First Major Opportunity
For Dr. Tam, the most immediate value of in vivo CAR T is not necessarily about creating a more sophisticated CAR. It is about changing who can realistically receive the therapy.
Current autologous CAR T therapies have demonstrated substantial benefits, particularly in hematological malignancies, but their cost and complexity remain significant barriers. In vivo approaches could potentially replace a highly individualized manufacturing process with a treatment that is produced and administered more like conventional medicine.
“Cost and accessibility are pretty intimately intertwined,” said Dr. Tam. “The primary advantage to the in vivo CARs will certainly immediately be felt on the accessibility.”
That accessibility could become particularly important if in vivo CAR T can deliver the efficacy associated with current CAR T therapies without requiring every patient to undergo an individualized manufacturing process.
Dr. Tam also sees a potential safety benefit, although he emphasized that this remains an area where evidence is still needed. Whether in vivo CAR T can reduce the prevalence or severity of cytokine release syndrome, for example, is an open question that will have to be answered clinically.
Treat Delivery as Part of the Therapeutic Design
The evolution of CAR engineering cannot be separated from the evolution of delivery. A highly effective CAR is of limited value if it cannot be delivered efficiently and selectively to the cells that need it.
Dr. Tam’s approach is to view the CAR and delivery platform as two technologies that can continue evolving independently while remaining compatible with one another. For Acuitas, that means developing targeted LNPs that can efficiently reach T cells while remaining sufficiently flexible to accommodate increasingly sophisticated payloads.
“I look at it as two separate pieces that can evolve and easily integrate with developments on the other side,” he said.
That flexibility matters because CAR designs are not standing still. As constructs gain additional specificities and other capabilities, the delivery platform needs to keep pace rather than becoming a constraint on therapeutic development.
For Acuitas, the goal is therefore to establish a delivery foundation that can support the next generation of nucleic acid medicines, rather than designing a delivery system around a single therapeutic concept.
Move CAR T Manufacturing Toward a Standard Process
One of the biggest potential changes from in vivo CAR T may happen outside the patient. Indeed, today’s autologous CAR T manufacturing process requires specialized infrastructure, highly trained personnel, and considerable coordination. The process also introduces a waiting period between collection and treatment that can be consequential for patients whose disease is progressing. A targeted lipid nanoparticle (LNP) approach could fundamentally change that model. “If we are able to realize in vivo CARs through something like a targeted lipid nanoparticle, it’s a much more uniform, standard manufacturing process,” said Dr. Tam.
The manufacturing model could potentially move toward a more standardized, batch-based process similar in some respects to other LNP medicines, while introducing additional requirements associated with targeted delivery and the therapeutic payload.
For developers, that shift could mean a move away from a patient-specific manufacturing paradigm toward a more standardized product. For patients, it could potentially mean faster availability and fewer logistical hurdles. “It really would be a game changer,” he shared.
Look Beyond mRNA to expand the Delivery Platform
The potential of lipid nanoparticles also extends well beyond CAR T. While many people became familiar with LNP technology through mRNA vaccines, Dr. Tam points to a much broader history of nucleic acid delivery. LNPs have also been used to deliver small interfering RNA (siRNA), including approaches designed to silence disease-causing genes.
Acuitas is building on that foundation by exploring delivery of increasingly sophisticated gene editing systems. Those efforts include systems designed to deactivate disease-causing genes, correct mutations with base editors and make more substantial changes to the genome using reverse transcriptase editors.
The same platform concept could eventually support RNA-based approaches in which the patient's own cells produce therapeutic proteins, including monoclonal antibodies. “We want to use our lipid nanoparticles to fully realize the potential, more generally, of nucleic acid-based medicines,” said Dr. Tam.
That broader ambition is also pushing LNP technology beyond its traditional association with the liver. Targeted nanoparticles designed to reach other tissues and cell types could open opportunities across a much wider range of diseases.
Solve Durability before Taking In Vivo CAR T into Oncology
There is, however, an important limitation that developers cannot overlook. For oncology, particularly diseases in which CAR T cells need to eliminate both substantial tumor burden and minimal residual disease, transient CAR expression may not be sufficient. Dr. Tam said Acuitas can efficiently deliver mRNA to T cells, with delivery reaching more than 50 percent of T cells in its work. The resulting CAR expression is robust, and the cells are active in animal models. The challenge is how long that expression lasts. “The one significant limitation we currently have on the mRNA side is that mRNA expression is transient,” said Dr. Tam.
That distinction could influence where in vivo CAR T first finds its strongest clinical opportunity. He believes current technology may be more accessible for autoimmune disease, where the therapeutic requirements may differ from those of cancer.
For oncology, the field will need technologies capable of providing much longer-lasting CAR expression or permanently installing the CAR into the appropriate cells.
Build Toward Permanent Genetic Programming
The encouraging part is that the technology needed to address that durability challenge is advancing. Dr. Tam pointed to reverse transcriptase editors, gene insertion systems, and transposon approaches as examples of technologies that could potentially enable more durable CAR expression. The ability to deliver these systems using LNPs is moving closer to what she described as a realistic expectation. “The ability to deliver and install those pieces with things like lipid nanoparticles is becoming or realistic than aspirational,” said Dr. Tam.
That could prove to be an important inflection point for in vivo CAR T. Instead of simply delivering mRNA that temporarily instructs T cells to express a CAR, future approaches could potentially use targeted delivery to establish longer-lasting genetic instructions.
For me, that is where this conversation becomes particularly important. The in vivo CAR T field is often framed around replacing the manufacturing complexity of today’s therapies, and that opportunity is substantial. But the path to making these therapies clinically meaningful will depend on more than eliminating the manufacturing bottleneck. It will require delivery platforms that can reach the right cells, carry increasingly sophisticated payloads and, for oncology, provide the durability needed to produce a sustained therapeutic response.
That is also why Dr. Tam’s perspective rounds out the conversations in this special series for Cell & Gene: The Podcast. Beam Therapeutics’ Gopi Shanker, Ph.D.; Precision Bioscience’s Cassie Gorsuch, Ph.D.; and Ascidian Therapeutics’ Mike Ehlers, MD, Ph.D., each shared why they are focused on advancing the therapies themselves, while Dr. Tam brings the delivery and platform perspective that sits underneath those therapeutic ambitions. His comments make clear that the success of in vivo CAR T will ultimately depend on whether the field can solve the delivery, durability, and manufacturing challenges at the same time. And he is optimistic that the surrounding technology is advancing quickly enough to address that challenge. “I think that there’s a lot of ancillary technology that is coming online faster and faster,” he said.
For an industry looking beyond the current boundaries of cell therapy, that may be the most important takeaway from my conversation with Dr. Tam. In vivo CAR T is not simply an evolution of the CAR. It is an intersection of cell engineering, nucleic acid technology, delivery and manufacturing, and progress in each will determine how quickly the field can move from an intriguing concept to a practical therapeutic platform.