In vivo CAR-T is considered a disruptive frontier technology precisely because it directly addresses the inherent pain points of existing ex vivo CAR-T therapies.

Traditional ex vivo CAR-T involves genetically modifying and expanding T cells outside the body, a process that is complex and costly. In contrast, in vivo CAR-T therapies utilize delivery systems such as viral vectors or nanoparticles to directly introduce the CAR gene into the patient's own T cells within the body, achieving in situ genetic modification and eliminating the need for external manufacturing steps.

This "off-the-shelf" universal production method, which also eliminates the requirement for lymphodepleting chemotherapy, holds the potential to enable large-scale clinical application of CAR-T. It not only significantly streamlines the production and treatment process and is expected to substantially reduce costs, but also can meet the clinical needs of more patients with acute or critical conditions, avoiding missed treatment windows due to lengthy manufacturing cycles.

Beyond these advantages, a key reason for significant excitement within the pharmaceutical industry about this technological direction is its potential to provide novel immuno-oncology therapies for cancers (including both hematological and solid tumors), as well as offer promising new treatment options for refractory chronic diseases like autoimmune disorders.

Lilly's strategic move specifically targets Orna's positioning in the field of in vivo cell engineering, particularly its exploration in autoimmune diseases.

In its announcement, Lilly pointed out that while early autologous CAR-T therapies have demonstrated therapeutic potential for autoimmune diseases, the complex ex vivo manufacturing process, high costs, and stringent logistical requirements limit their accessibility to a broader patient population. The collaboration with Orna aims to "unlock new genetic medicines and cell therapies" for patients with limited or no treatment options.

Delving into Orna's background, the company originated from the pioneering research of Dr. Alex Wesselhoeft and Dr. Daniel G. Anderson at the Massachusetts Institute of Technology (MIT). It was subsequently founded by MPM Capital and its investment management affiliate, BioImpact Capital.

Orna officially launched on February 24, 2021, following an $80 million Series A financing round. The round was co-led by MPM Capital, Taiho Ventures, and F2 Ventures, with key strategic investors including Kite (a Gilead company), Bristol Myers Squibb, Astellas Venture Management, the Novartis Institutes for BioMedical Research, and the PAGS Group.

Orna's technological distinctiveness lies in its engineered circular RNA (oRNA®) platform. By circularizing linear RNA within cells to form stable structures, the platform aims to enhance RNA expression efficiency in vivo. This approach holds the potential to unlock therapeutic applications currently unattainable with existing ex vivo cell therapies.

Meanwhile, Orna has been continuously strengthening its delivery system capabilities. In May 2024, Orna announced the acquisition of ReNAgade Therapeutics, a company focused on RNA delivery. The latter has already achieved targeted delivery to extrahepatic tissues in non-human primate models.

Following the integration, Orna plans to combine its circular RNA technology, novel LNP delivery systems, and RNA editing tools to build a differentiated in vivo CAR-T platform, covering areas such as oncology and autoimmune diseases.

In terms of pipeline development, Orna's leading candidate, ORN-252, is a CD19-targeted in vivo CAR-T therapy. It has completed preclinical studies and is ready to enter clinical trials immediately. It is intended for treating various B cell-mediated autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

Regarding industrialization, Orna enhances the validation of its technology through external collaborations. In 2022, Merck entered into multiple collaborations with Orna for circular RNA therapies, covering vaccine and therapeutic areas. In early 2023, Orna also partnered with the Chinese company Senobio, granting the latter access to certain projects of Orna's breakthrough isCAR technology. In return, Orna gained opportunities for investigator-initiated clinical trials in China, accelerating the validation of selected projects in patients.

Through this acquisition, Lilly has acquired Orna's integrated capabilities in circular RNA, LNP delivery, and in vivo immune cell engineering, completing a systematic strategic layout just before the critical juncture of clinical translation in the in vivo CAR-T field.

With Lilly entering the fray, all major MNCs have now positioned themselves in the frontier field of in vivo CAR-T, aggressively securing their stakes through diverse strategies. At a glance, in vivo CAR-T has unmistakably become an MNC "battleground," where giants are wagering vast resources on technology, platforms, speed, and therapeutic potential.

AbbVie first partnered with Umoja Biopharma in a $1.44 billion deal to collaborate on in vivo CAR-T oncology programs based on lentiviral vectors. Then, in June of last year, it made a bold $2.1 billion all-cash acquisition of Capstan Therapeutics, a company focused on the LNP (lipid nanoparticle) delivery route. This move effectively secured both major technological pathways for in vivo CAR-T.

Umoja has developed a proprietary VivoVec™ platform. This platform utilizes a lentiviral vector delivery system. The VivoVec vectors are enhanced through Umoja's proprietary Multi-Domain Fusion (MDF) surface engineering, which improves their binding, activation, and transduction capabilities for T cells. Furthermore, the vectors employ a VivoVec Cocal fusion glycoprotein pseudotype. This Cocal fusion glycoprotein exhibits resistance to inactivation by human serum, allowing VivoVec-based drug products to achieve high potency.

Umoja's VivoVec platform is being developed for CAR-T therapies targeting indications in both autoimmune diseases and hematological malignancies. AbbVie's collaboration with Umoja focuses on the hematological oncology applications of VivoVec CAR-T. The most advanced program in their collaboration is the in vivo CD19 CAR-T candidate UB-VV111, which has already progressed to Phase I clinical trials. The collaboration also includes two other, undisclosed preclinical projects.

Capstan Therapeutics, on the other hand, is a prominent in vivo CAR-T development company. Founded in 2022, its founders include CAR-T pioneer Bruce Levine and the "Father of CAR-T," Carl June. The company specializes in developing RNA-based in vivo CAR-T cells (tLNP-RNA) using its proprietary targeted lipid nanoparticles (tLNPs). Notably, major pharmaceutical players including Pfizer, Bayer, Eli Lilly, Bristol Myers Squibb (BMS), Novartis, and Johnson & Johnson have invested in Capstan.

Public information indicates that Capstan's development pipeline covers both autoimmune diseases and oncology. Its primary asset is CPTX2309, a tLNP-CD19 CAR T mRNA, currently undergoing a clinical study in healthy human subjects. AbbVie's strategic focus for Capstan's future development is reported to be more concentrated on autoimmune diseases.

AstraZeneca has also made a significant move. In March 2025, it announced the acquisition of EsoBiotec in a deal with a total value of up to $1 billion. Through this acquisition, AstraZeneca gained access to EsoBiotec's core Engineered Nanobody Lentiviral (ENaBL) platform and four of its research and development pipelines.

EsoBiotec's most advanced pipeline asset, ESO-T01, is a nanobody-targeted, immunologically shielded lentiviral vector. It carries a humanized BCMA single-domain antibody CAR for in vivo T cell engineering. While primarily developed for multiple myeloma, its potential indications also include autoimmune diseases.

ESO-T01 was co-developed by EsoBiotec and Pregene. It combines EsoBiotec's proprietary ENaBL platform with Pregene's patented anti-BMCA single-domain antibody.

In July of last year, The Lancet published the results of an Investigator-Initiated Trial (IIT) involving EsoBiotec's platform technology in four multiple myeloma patients. The data showed an Overall Response Rate (ORR) of 100%, with two patients achieving stringent Complete Remission (sCR) and two achieving Partial Response (PR). These results represent a significant early breakthrough in the field of in vivo CAR-T therapy.

Following closely, Gilead also swiftly entered the field. Its subsidiary, Kite, first acquired Interius BioTherapeutics for $350 million, and then secured a collaboration with the Chinese company Pregene with an upfront payment of $120 million and a total deal value of $1.64 billion, marking the largest out-licensing deal for in vivo CAR-T from China.

Interius's proprietary LENTIVECTOR platform is a lentiviral vector delivery system. By engineering the viral vector, it enables precise, targeted delivery of exogenous genes to specific cells for in vivo cellular reprogramming.

Based on the LENTIVECTOR platform, Interius has developed a series of pipeline assets, including in vivo CAR-T and in vivo CAR-NK therapies, with indications spanning both autoimmune diseases and oncology.

Its lead project, NT2104, utilizes a programmable vector to specifically target CD7-positive T cells and NK cells. It delivers and transduces a CD20 CAR gene, thereby generating CAR-T and CAR-NK cells in vivo to target and kill tumor cells expressing CD20. Currently, NT2104 has advanced to the clinical stage and is undergoing a Phase I clinical study in Australia and Germany.

Bristol Myers Squibb (BMS) also strengthened its cell therapy portfolio with a $1.5 billion all-cash acquisition of Orbital Therapeutics.

Orbital Therapeutics focuses on advancing a broad portfolio of RNA medicines. Its initial focus was on autoimmune diseases, with expansion into oncology, next-generation vaccines, and protein-based therapies. Its development later concentrated on in vivo CAR-T, leveraging its RNA platform to reprogram immune cells (such as T cells) in vivo to express CARs or other immunomodulatory proteins.

Orbital's lead project is an in vivo CAR-T cell therapy, OTX-201. OTX-201 contains an optimized circular RNA encoding a CD19-targeting CAR, delivered via targeted lipid nanoparticles (LNPs) for expression within the body. It is primarily being developed to treat B cell-driven autoimmune diseases. Currently in the IND-enabling study stage, it is planned to initiate clinical trials in the first half of 2026.

From these transactional trends, it is evident that MNCs are generally willing to pay a higher premium for in vivo CAR-T platforms based on the LNP-RNA pathway, and circular RNA platforms are becoming a new focal point of interest—the two most recent acquisitions (Orbital and Orna) both involved circular RNA companies.

Furthermore, regarding indication focus, MNCs are particularly optimistic about the therapeutic potential of in vivo CAR-T for autoimmune diseases. The core of treating autoimmune diseases lies in eliminating pathogenic B cells and re-establishing immune tolerance. In theory, in vivo CAR-T therapy, through transient or controllable CAR expression, could provide an effective and safe solution for autoimmune diseases.

While MNCs are investing heavily to plant their flags early on this strategic high ground that is reshaping the industry, a wave of Chinese innovative biopharmaceutical companies are simultaneously launching a full-scale offensive in this cutting-edge "arms race," striving to carve out a Chinese position on the map of next-generation therapies.

Leveraging the world's largest pool of unmet clinical needs, accumulated engineering capabilities, the support of investigator-initiated trial (IIT) innovation mechanisms, and formidable execution power, Chinese companies have initiated a "saturation-style R&D" assault in the field of in vivo CAR-T. Over 200 companies are now involved, encompassing firms in cell therapy, mRNA, antibody development, and traditional pharmaceuticals alike.

Late last month, domestic companies took another step forward in this race, with the first in vivo CAR-T product receiving clinical trial approval in China: SYS6055 injection, developed by CSPC Pharmaceutical Group, was approved for clinical trials targeting relapsed/refractory aggressive B-cell lymphoma.

SYS6055 injection utilizes a lentiviral vector to directly generate CD19-targeting CAR-T cells in vivo, enabling specific recognition and elimination of target cells to achieve therapeutic goals. Given its mechanism, its indications have the potential to expand to other CD19-positive B-cell malignancies and autoimmune diseases.

Preclinical studies demonstrated that SYS6055 injection can generate CAR-T cells specifically in vivo, exhibiting significant tumor suppression effects, a favorable safety profile, and advantages in cost and time.

Almost simultaneously, the Center for Drug Evaluation (CDE) expert committee published a guidance document, providing the first "instruction manual" for in vivo CAR-T development in China, outlining and standardizing the R&D pathway. These dual advancements in clinical progress and regulatory guidance mark the official entry of in vivo CAR-T, a frontier technology, into a new phase of coordinated clinical and regulatory advancement within China.

This review article, titled "Research Progress and General Considerations for Non-Clinical Studies of In Vivo Chimeric Antigen Receptor T Cells," was published in the Chinese Journal of Drug Evaluation. Authored by experts from the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA), it systematically provides scientific guidance for the research, development, and evaluation of this frontier field.

The article deeply analyzes the unique challenges posed by in vivo CAR-T's dual nature as both a gene therapy and a cell therapy. Accordingly, the review explicitly proposes "Risk-based" and "Case-by-case" as core evaluation principles. It advocates that non-clinical studies should be flexibly designed around the specific characteristics of each product (such as viral/LNP vector type, integration properties, etc.).

Simultaneously, the article presents systematic considerations for pharmacology, pharmacokinetics (with a focus on biodistribution), and complex safety assessments (including immunotoxicity, genotoxicity, etc.). It particularly discusses practical strategies for situations where relevant animal species are lacking (e.g., using surrogate products or integrated study designs).

The publication of this review reflects the regulatory agency's balanced approach to fostering technological innovation while managing potential risks. It provides a clear and actionable framework for non-clinical research pathways, guiding in vivo CAR-T products from the laboratory to the clinic and laying a solid regulatory science foundation for the industry's standardized and high-quality development.

Beyond the recent breakthroughs mentioned above, Chinese companies have also previously disclosed promising forward-looking data based on Investigator-Initiated Trials (IITs).

In September last year, Hongxin Biotech released clinical trial data for its mRNA-LNP-based in vivo CAR-T candidate HN2301 in patients with systemic lupus erythematosus (SLE). This marked the first clinical validation in humans for an in vivo CAR-T therapy based on the mRNA-LNP pathway.

The data showed that dosing in two low-dose patients preliminarily demonstrated the safety of single and multiple administrations at low doses. It also observed CAR-T generation and a certain degree of B cell clearance, confirming that with repeated dosing, CAR-T expression and B cell clearance were achievable, preliminarily proving the feasibility of repeated administration in humans. Dose-escalation studies further highlighted promising therapeutic potential.

Three months later, Weitao Biotech, a company spun off from the in vivo CAR-T platform of Shali Biotech, also released IIT data for its in vivo CAR-T therapy GT801, developed using a targeted LNP delivery system, for the treatment of relapsed/refractory CD19-positive B-cell lymphoma.

As of November 30, 2025, two non-Hodgkin lymphoma patients—who did not receive lymphodepletion pretreatment and completed three doses of 0.5mg each and four doses of 1.5mg each, respectively—showed good overall clinical tolerance. High levels of CAR expression were observed in peripheral blood T cells, with persistent and reproducible effective expansion of CAR-T cells after each administration. Notably, no CAR expression was detected in peripheral blood mononuclear cells, indicating no off-target delivery risk for GT801 and confirming that this delivery platform can sufficiently enhance targeting efficiency while avoiding non-specific uptake.

Previously, an investor noted, "If this endeavor can succeed in principle, the probability of it happening in China is very high."

In their view, in vivo CAR-T ultimately competes on scientific innovation capability. "The scientific difficulty in this field is very high; it likely doesn't follow a simple imitation logic. What everyone has in hand now can be called version 1.0. Success might require versions 2.0, 3.0, or even 5.0," estimating it may take another one to two years or even longer.

Overall, although the technological pathways are not yet fully mature and clinical validation remains in its early stages, the joint push from domestic and international companies alongside regulatory agencies has rapidly propelled in vivo CAR-T from a laboratory concept into the deep waters of clinical exploration.

This race is no longer just a contest of capital; it is a comprehensive competition encompassing underlying technology, translational efficiency, and clinical insight. The combined force of science, capital, and clinical demand is driving this cell therapy revolution further and deeper. Ultimately, the flag of victory may be planted on the ground of those who can truly bring accessible and affordable transformative therapies to patients.