Why the Industry Is Moving Toward In Vivo CAR-T

Ex vivo CAR T therapy has delivered some of the most impressive outcomes in modern medicine, particularly in hematologic malignancies. However, the manufacturing process remains one of the modality's biggest challenges. Each treatment requires a complex series of patient-specific steps, including leukapheresis, T-cell isolation and activation, genetic modification, cell expansion, quality control testing, cryopreservation, shipment, and reinfusion. This individualized workflow can take several weeks, requires highly specialized GMP facilities, and contributes significantly to the overall cost of therapy. Manufacturing failures, logistical complexities, and patient deterioration during the vein-to-vein interval remain persistent industry concerns.

Beyond operational challenges, ex vivo CAR T also faces scalability limitations. As demand for cell therapies expands beyond hematologic cancers into autoimmune and other indications, the industry's ability to manufacture individualized products at commercial scale becomes increasingly difficult. Each batch is effectively a batch of one, creating constraints on manufacturing capacity, process standardization, supply chain efficiency, and patient access. These limitations have prompted developers to explore approaches that can deliver the benefits of CAR T without the burden of bespoke manufacturing.

In vivo CAR T has emerged as a promising solution. Rather than collecting and engineering T cells outside the body, in vivo approaches use targeted delivery technologies, including lentiviral vectors, adeno-associated viral vectors (AAVs), and lipid nanoparticles (LNPs), to deliver CAR genetic material directly to immune cells within the patient. The objective is to generate functional CAR-T cells in situ, effectively shifting the manufacturing process from the facility to the patient. Advances in vector engineering, cell-targeting strategies, and nucleic acid delivery technologies have accelerated the feasibility of this approach and positioned in vivo CAR-T as one of the most active areas of next-generation CGT development.

The potential benefits are significant. By eliminating many of the labor-intensive manufacturing steps associated with ex vivo therapies, in vivo CAR T could reduce manufacturing complexity, lower cost of goods, shorten time to treatment, simplify logistics, and improve accessibility. In addition, the ability to manufacture delivery vectors or nanoparticles in larger, standardized batches may provide greater scalability and consistency than patient-specific cell manufacturing. Some platforms may also enable repeat dosing strategies, creating a level of therapeutic flexibility that is difficult to achieve with conventional autologous CAR-T therapies.

However, the transition to in vivo CAR-T is much more than a manufacturing innovation. It represents a fundamental shift in how the industry approaches chemistry, manufacturing, and controls (CMC). In traditional CAR-T programs, CMC efforts are largely focused on controlling the quality of the engineered cell product, including cell identity, viability, phenotype, transduction efficiency, and functional activity. In contrast, in vivo CAR-T developers must focus on the delivery system itself. Critical quality attributes increasingly center on vector integrity, particle characteristics, payload stability, targeting specificity, transduction efficiency, biodistribution, and the ability to reliably generate the desired CAR-T population within the patient. This requires new analytical methods, potency strategies, and process control approaches that draw heavily from both gene therapy and biologics development.

What this changes for CMC

No ex vivo patient-cell manufacturing or cell-product release. The gene-delivery product becomes the primary CMC control point — its potency, targeting/selectivity, purity and consistency directly influence clinical performance and patient safety.

The regulatory implications are equally profound. Regulators will no longer evaluate only the quality of a manufactured CAR-T cell product but also the safety and performance of the delivery platform responsible for generating those cells in vivo. As a result, developers should anticipate increased scrutiny around biodistribution, off-target transduction, vector persistence, immunogenicity, genomic integration risks, and long-term safety monitoring. Demonstrating where the genetic payload travels, which cell populations are modified, how long CAR expression persists, and whether unintended tissues are affected will become central components of both nonclinical and clinical development programs.

Ultimately, the industry's shift toward in vivo CAR-T reflects a broader convergence of cell therapy, gene therapy, and advanced delivery technologies. The challenge is no longer simply manufacturing a consistent CAR-T product outside the body. Instead, success depends on developing delivery platforms that can reproducibly, safely, and effectively generate the right CAR-T cells within the patient. For CGT organizations, this evolution will require new capabilities in delivery science, analytics, CMC strategy, regulatory affairs, and translational medicine. Those that can successfully integrate these disciplines will be well positioned to lead the next generation of CAR-T innovation.