Can in vivo engineering move CAR-T from individualized manufacturing toward a more standardized and scalable therapeutic model?
March 6, 2026
Over the past two years, cell therapy has seen growing interest in new platform approaches. Lilly’s agreement to acquire Orna Therapeutics, AbbVie’s acquisition of Capstan Therapeutics, and Bristol Myers Squibb’s acquisition of Orbital Therapeutics reflect increasing industry attention to in vivo CAR-T and related in vivo cell-engineering technologies.
Traditional ex vivo CAR-T can carry price tags in the hundreds of thousands of dollars and requires a complex, individualized manufacturing process. In vivo CAR-T is being explored as a different model: generating engineered immune cells directly in the patient, with the potential to reduce some of the manufacturing and logistical constraints associated with ex vivo production.
1. What Is In Vivo CAR-T and How Does It Differ From Ex Vivo CAR-T?
Since the first CAR-T products were approved in 2017, CAR-T therapy has established a strong efficacy benchmark in hematologic malignancies. From a commercial perspective, however, conventional ex vivo CAR-T has remained constrained by structural limitations. A single treatment can cost roughly $400,000 to $500,000; manufacturing can take three to four weeks; and production quality depends heavily on each patient’s starting cells.
This individualized model creates manufacturing, CMC, quality-control, and logistical complexity that can make broader-scale deployment challenging. These constraints are among the factors driving interest in approaches that could simplify production and delivery.
Allogeneic CAR-T has pursued an off-the-shelf model, but clinical development continues to address challenges including graft-versus-host disease, host-versus-graft immune rejection, and treatment persistence. Against this backdrop, in vivo CAR-T has emerged as another approach being investigated to reduce reliance on individualized manufacturing.
In February 2026, Lilly agreed to acquire Orna Therapeutics, with Orna shareholders eligible to receive up to $2.4 billion in cash, including milestone-based payments. AbbVie announced its $2.1 billion acquisition agreement for Capstan Therapeutics in June 2025 and completed the acquisition in August 2025. Bristol Myers Squibb announced its acquisition of Orbital Therapeutics in October 2025 and completed the transaction in December 2025.
The strategic message is straightforward: in vivo CAR-T has moved beyond a purely preclinical concept, with early clinical programs beginning to test the approach in humans. Whether it can change the manufacturing model and economics of cell therapy will depend on clinical safety, efficacy, and reproducibility.
2. How In Vivo CAR-T Works: Delivery Systems and CAR Expression
The basic logic of in vivo CAR-T is to use the patient’s own circulation as the biological environment in which immune cells are reprogrammed. The core challenge therefore shifts away from sterile cell culture and ex vivo cell selection toward delivering CAR-encoding genetic information safely and efficiently to specific T-cell populations inside the body.
Targeted Lipid Nanoparticles for In Vivo CAR-T
Current in vivo CAR-T delivery approaches can be broadly divided into non-viral and viral systems, with targeted lipid nanoparticles (tLNPs) attracting particular attention.
Conventional LNPs, including those used for COVID-19 vaccines, tend to accumulate in the liver after intravenous administration. To reprogram circulating T cells, developers must overcome this liver tropism. Capstan’s approach, for example, uses targeting ligands on the LNP surface—such as antibodies, antibody fragments, or peptides—to increase delivery to selected T-cell populations.
Non-Integrating RNA Expression
With non-integrating RNA payloads, CAR expression is temporary rather than permanent, although duration can vary by construct; circular RNA platforms are being developed in part to extend protein expression relative to conventional mRNA. In oncology, limited persistence can be a disadvantage if durable CAR activity is required. From a safety and drug-development perspective, however, non-integrating expression may reduce risks associated with permanent genomic modification and may allow repeat dosing if the delivery platform does not trigger limiting immunity.
DNA and Integrating Approaches
Some programs are exploring in vivo delivery of CRISPR-Cas9 or transposon systems to create durable genomic integration and potentially long-term CAR expression after a single administration. But when cells cannot be purified and quality-controlled before reinfusion, off-target editing and random genomic insertion create a higher safety and regulatory bar. These approaches remain earlier in development.
3. In Vivo CAR-T in Autoimmune Disease and Beyond Cancer
The potential applications of in vivo CAR-T may extend beyond hematologic malignancies. Autoimmune disease has become one area of particular clinical and industry interest.
Clinical work with conventional CD19 CAR-T has reported deep B-cell depletion and drug-free remissions in some patients with severe, treatment-refractory autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis. The durability and generalizability of these responses are still being defined.
Using conventional ex vivo CAR-T in chronic autoimmune disease raises a different risk-benefit and access equation than in life-threatening malignancies. Cost, manufacturing complexity, lymphodepletion, prolonged B-cell depletion, and infection risk are among the considerations being evaluated.
mRNA-based in vivo CAR-T offers a theoretical alternative. A targeted mRNA-LNP could drive temporary CAR expression, produce a strong pulse of B-cell depletion, and then fade as the mRNA degrades. In principle, this could enable deep depletion while limiting prolonged CAR activity, but whether it produces a durable immune reset without unacceptable immune suppression remains a clinical question.
If this concept holds up clinically, in vivo CAR-T could enter autoimmune markets currently served by monoclonal antibodies, bispecifics, and small-molecule therapies, while potentially avoiding the individualized manufacturing process required by ex vivo CAR-T.
4. In Vivo CAR-T Manufacturing and Platform Economics
In in vivo CAR-T, the underlying delivery platform may have value across multiple programs. If a tLNP or engineered viral system demonstrates reliable targeted delivery in humans, parts of the platform could potentially be adapted to different targets or payloads, although each product would still require its own development and validation.
This modularity could allow parts of a validated delivery platform to be reused across programs, although targeting, payload, CMC, safety, and regulatory requirements may still need to be re-optimized for each product. It also helps explain why large pharmaceutical companies have shown interest in acquiring platform capabilities rather than only individual programs.
Traditional ex vivo CAR-T requires an individualized manufacturing cycle for each patient, with substantial labor, quality-control, and logistical requirements. In vivo CAR-T—particularly LNP-based approaches—could move parts of production closer to standardized nucleic-acid manufacturing. Whether this translates into meaningfully lower cost at commercial scale remains to be demonstrated.
5. What Biotech and Pharma Teams Are Watching in In Vivo CAR-T
Biotech: Platform Innovation and Freedom to Operate
The intellectual-property landscape around ionizable lipids, targeting technologies, and nucleic-acid delivery is crowded. For companies developing new platforms, formal, asset-specific freedom-to-operate analysis is therefore important.
For emerging biotechs, differentiation may come from areas such as proprietary ionizable lipids, improved targeting systems, or RNA designs that enhance translation efficiency. Preclinical biodistribution and target-cell data can also be important in evaluating the potential of a platform.
Pharma: Building In Vivo Cell-Engineering Capabilities
Because in vivo cell engineering spans targeting ligands, delivery vehicles, nucleic-acid design, CMC, and clinical development, companies may combine internal capabilities with acquisitions and partnerships as they build programs in the field.
What Comes Next for In Vivo CAR-T?
Despite the enthusiasm, in vivo CAR-T remains at an early stage. Most programs are still in preclinical or early clinical development, and the decisive turning point will come from detailed human data.
Key metrics include the actual proportion of T cells engineered in vivo, protein expression in off-target tissues such as the liver and lungs, the pharmacokinetic profile of CAR expression, and whether immune responses against the delivery vehicle or CAR construct limit repeat dosing.
Many advances in medicine have depended not only on new biological targets, but also on improved ways of delivering therapy. In vivo CAR-T is being explored as one way to reduce dependence on individualized ex vivo manufacturing and move cell therapy toward a more standardized model. Significant clinical, manufacturing, and regulatory questions remain, and the field is still early, but the level of industry investment indicates sustained interest in testing the approach.
Why This Matters
For cell-therapy and immunology teams, a central question is whether targeted delivery can become reliable and reproducible enough in humans to support a practical therapeutic platform. The answer will help determine how broadly in vivo CAR-T can expand beyond today’s individualized cell-therapy model.
References
• AbbVie. AbbVie to Acquire Capstan Therapeutics. June 30, 2025.
• Bristol Myers Squibb. Acquisition of Orbital Therapeutics announced October 10, 2025.
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