In Vivo CAR-T Fuels Upstream Industry Players?

The popularity of in vivo CAR-T is rising rapidly.

Since the beginning of the year, MNCs have been actively making moves in this field: On March 17, AstraZeneca announced a total acquisition of EsoBiotec for $1 billion to establish a presence in the in vivo CAR-T therapy space. On June 30, AbbVie announced the acquisition of in vivo CAR-T company Capstan Therapeutics for up to USD 2.1 billion in cash. This marks the second major M&A deal in the in vivo CAR-T field following AstraZeneca. On August 21, Kite, a subsidiary of Gilead, further announced a $350 million acquisition of Interius to bolster Kite's pipeline in the cell therapy arena.

The strategic layout of several multinational corporations (MNCs) in this cutting-edge field indicates that the development of in vivo CAR-T is starting to accelerate. Behind this change lies increasingly mature delivery vector technology. As new therapies gradually become a reality, technology partners along the industry chain will also attract greater attention.

Traditional CAR-T therapy requires extracting T cells from the patient, genetically modifying and expanding them in vitro, and then reinfusing them back into the patient's body. The main value lies at the cellular level, involving cell processing and expansion. In vivo CAR-T therapy modifies T cells directly within the patient's body after injection, involving gene-level technologies. As a result, the collaboration ecosystem has shifted toward delivery technologies and nucleic acid platforms, with targeted delivery efficiency and safety emerging as key areas of industry focus.

Changes in technical pathways are expected to bring about the restructuring of upstream partners.

Lentiviral vectors, initially modified from the human immunodeficiency virus (HIV), are a relatively safe and efficient gene therapy vector. Lentiviral vectors can permanently integrate the CAR gene into the genome of host T cells, enabling long-term stable expression that remains even after cell division and proliferation. The core technology platforms of EsoBiotec, acquired by AstraZeneca, and Interius, acquired by Kite, a subsidiary of Gilead, are both based on lentiviral vectors.

Interius develops in vivo cell therapies using engineered lentiviral vectors, with its current core product being INT2104. INT2104 delivers CAR genes via lentiviral vectors and directly generates effector CAR-T cells and CAR-NK cells in vivo, thereby enabling precise targeting of B-cell malignancies.

The core technology of EsoBiotec, acquired by AstraZeneca, is the Engineered Nanobody Lentivirus (ENaBL) platform. Building on traditional lentiviral vectors, ENaBL goes a step further by anchoring nanobodies on the vector surface, enabling the specific recognition and transfection of immune cells through nanobodies.

The acquisition value of EsoBiotec has reached $1 billion, which is significantly higher than Interius' $350 million. This largely reflects the value of the ENaBL platform.

Currently, there are quite a few companies in China engaged in the development of lentiviral vector platforms: for instance, Pregene Biopharma was involved in the development of EsoBiotec's ESO-T01 product. Additionally, IASO Biotherapeutics, Genocury, Immunofoco, and Legend Biotech also have a presence in the lentiviral vector field.

The official website of IASO Biotherapeutics shows that the company has two in vivo CAR-T products under development: one is IASO-301, a CD22-targeting product co-developed with Umoja, and the other is IASO-140, which targets BCMA/GPRC5D. Both products are currently in the early clinical stage.

Genocury's in vivo CAR-T technology platform, VivoExpress, is an in vivo targeted delivery CAR-T preparation technology based on lentivirus development. This technology platform can precisely and efficiently target and infect T cells while effectively avoiding the infection of bystander cells, demonstrating good safety. Currently, Genocury's JY231 is in the early exploratory clinical research stage.

Immunofoco has developed a novel in vivo technology platform. Compared with traditional VSV-G pseudotyped lentiviral vectors, the new lentiviral vector pseudotyped with MxV glycoprotein (MxV-G) demonstrates significant advantages in key performance indicators such as viral titer, T-cell transduction efficiency, and cytotoxic activity. It not only enhances the production yield and infection efficiency of viral vectors but also improves the ability to effectively recognize and kill tumor cells.

Due to the high development difficulty and complex mechanism of CAR-T, development companies are more dependent on upstream CXOs. According to statistics, over 65% of projects in the CGT field involve CXO companies.

Of course, from ex vivo CAR-T to in vivo CAR-T, the requirements for lentiviral vectors have also increased. On the basis of having stronger specificity, the delivery efficiency must also be higher. Only by meeting such conditions can lentiviral vectors deliver the CAR gene to a sufficient number of target cells, achieving therapeutic effects while ensuring safety.

In vivo CAR-T therapy, the advantage of lentiviral vectors lies in achieving long-lasting CAR expression, with effects lasting for months. The potential disadvantage may be related to safety aspects, such as the risks associated with gene integration. The risk of gene integration may also pose challenges to the approval and market entry of products related to the lentiviral vector route. In contrast, another route—LNP (lipid nanoparticle)—has recently begun to attract more attention.

Currently, in the field of in vivo CAR-T, all LNP-delivered payloads are mRNA that can generate CAR. mRNA directs protein production within cells, avoiding the risks associated with permanent genetic alterations, thus offering higher safety. Additionally, mRNA has a half-life, meaning that if severe side effects occur during treatment, CAR activity can disappear within days after discontinuation of the drug. Of course, this also implies that repeated dosing is necessary to sustain CAR activity if continuous expression is desired.

LNP is the core delivery system of the COVID-19 mRNA vaccine and has thus gained widespread recognition. The recent rise in interest in in vivo CAR-T is also related to the advancement of LNP delivery technology. When LNP encounters the cell membrane, it is engulfed into the cell. As the internal pH changes, the mRNA is released from the particles and guides protein synthesis. Some investors believe that the prior approval experience of mRNA vaccines will facilitate the regulatory approval and market entry of in vivo CAR-T products using the mRNA-LNP approach.

The CAR-T company Capstan, acquired by AbbVie, focuses on the LNP approach.

Capstan Therapeutics, co-founded by Nobel laureate Drew Weissman, CAR-T pioneer Carl June, and other scientists, focuses on delivering mRNA through targeted lipid nanoparticles (tLNP). The company's leading candidate drug, CPTX2309, is intended for the treatment of autoimmune diseases and entered Phase I clinical trials in June this year for B cell-mediated autoimmune conditions.

A considerable number of domestic companies are actively engaged in the in vivo CAR field based on the LNP approach. According to incomplete statistics from VCBeat, companies such as CSPC, Everest Medicines, 3D Medicines, Immorna, INNORNA, METiS Pharmaceuticals, ABOGEN, Starna Therapeutics, GRIT Biotechnology, MagicRNA, and Simnova are all involved.

SYS6020, developed by CSPC, is based on proprietary mRNA-LNP technology. SYS6020 is capable of expressing a chimeric antigen receptor (CAR) that specifically recognizes the BCMA antigen. This CAR then enables targeted recognition and elimination of BCMA-positive B cells and plasma cells in patients, preventing the production of harmful autoantibodies and thereby achieving the therapeutic goal. In June 2024, SYS6020 was approved for clinical use in China for the first time., intended to develop treatments for relapsed or refractory multiple myeloma.

JCXH-213, an in vivo CAR drug developed by Immorna, targets CD19 for the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma. In March this year, JCXH-213 completed the first patient dosing.。

MagicRNA successfully establishes engineered cell targeted delivery platform (EnC-LNP), providing strong support for precise delivery of nucleic acid drugs. The in vivo CAR-T pipeline developed based on the EnC-LNP platform completed the first administration to a patient with Systemic Lupus Erythematosus (SLE) in the first quarter of 2025.

Starna Therapeutics has currently accumulated a library of over three thousand novel cationic lipid molecules and screened tens of thousands of lipid nanoparticles. Based on its proprietary mRNA and targeted LNP delivery technology platform, Starna Therapeutics has developed an in vivo CAR-T product (STR-P004), which has entered the clinical trial phase.

In addition to the few companies with advanced clinical development progress mentioned above, more companies are rushing into the mRNA-LNP field.

The autologous CAR-T generation program developed by Everest Medicines based on its independently researched and developed tLNP system has achieved multiple preclinical validation results. It is expected to confirm the clinical candidate molecule in the second half of this year and is likely to obtain the first-in-human clinical data in 2026.

Deeply convinced of the potential, INNORNA has also chosen to independently build an LNP technology platform. It has currently constructed a resource library containing over 5,000 ionizable lipids for screening LNP carriers suitable for different therapeutic scenarios. The diversity-oriented lipid library offers greater molecular diversity, significantly increasing the likelihood of discovering lipids with novel functionalities, thereby enhancing the overall efficiency and success rate of the LNP platform.

In addition, Simnova Biotechnology has entered into a collaboration with Orna. Leveraging Orna's extensive expertise in the fields of circular RNA and LNP, the two parties will jointly research and develop next-generation in vivo CAR-T products, including Orna's fastest-advancing in vivo CAR-T product, ORN-101, which targets CD19.

As the popularity of in vivo CAR-T continues to rise, upstream CXO companies have also begun to come into the spotlight. Compared with the risks faced by product development companies, enterprises in the upper stream of the industrial chain offer greater certainty.

In the field of in vivo CAR-T, representative companies providing CXO services in China are Obio Technology and Porton Advanced.

Obio Technology has over a decade of experience in the cell and gene therapy field, possessing technology platforms and scalable production capabilities such as the AAVNeO novel AAV vector development technology, LVVNeO lentivirus screening platform, and LNPNeO novel nucleic acid drug delivery platform. In the lentivirus field, while developing high-yield suspension lentivirus cell lines, Obio Technology has also successfully developed a large-scale production process system for lentiviral vectors based on fixed-bed reactors, further enhancing the efficiency of large-scale lentivirus production, improving yield stability, and increasing the purity of the viral product.

Obio Technology develops a variety of vectors, including adeno-associated viruses (AAVs), oncolytic viruses, plasmids, lentiviruses, mRNA, and lipid nanoparticles (LNPs). It also provides one-stop CRO/CDMO services, covering all stages of drug development: drug discovery, preclinical pharmaceutical research, sample production for early-phase and confirmatory clinical trials, pre-commercial process characterization and process validation, as well as commercial manufacturing. To date, Obio Technology has served over 14,000 R&D laboratory customers, undertaken more than 540 cell and gene therapy CDMO projects, and its service experience ranks among the top in the domestic industry.

Porton Advanced can also provide customers with one-stop service solutions for gene and cell therapy drugs throughout the entire lifecycle from preclinical research to drug commercialization. Porton Advanced has established CRO and CDMO platforms for plasmids, viral vectors, cell therapy, gene therapy, and nucleic acid therapy, with R&D and production facilities covering a total area of over 20,000 square meters and 10 viral vector production lines. Its clients span across countries including China, the United States, and New Zealand.

In the field of in vivo CAR-T, Porton Advanced can support both mRNA-LNP and lentivirus process routes. Porton Advanced assists clients in LNP screening during the early stages of research and development, and possesses the capability for process development and GMP production of in vivo CAR-T projects.

As the research in the in vivo CAR-T field is still in its early stages, the revenue that these two CXO companies can generate from the in vivo CAR-T business is negligible. A person familiar with the in vivo CAR-T field told VCBeat.

In addition to comprehensive service providers like Obio Technology and Porton Advanced, many small CXO companies in niche fields are also expected to benefit in the future.

For example, 3D Medicines (01244.HK) has established a partnership with nucleic acid CDMO company Catug Biotechnology. 3D Medicines' self-developed mRNA R&D platform and liposome delivery system (3D-LNP) can be combined with Catug Biotechnology's advantages and experience in scalable mRNA production to accelerate the advancement of in vivo CAR-T research and development.

METiS Pharmaceuticals advances its in-house pipeline while also providing delivery systems and liposome solutions to external partners. METiS Pharmaceuticals' AiLNP+AiRNA platform can simulate and predict the in vivo behavior of nanoparticles and mRNA, including key parameters such as biodistribution, cellular uptake, endosomal escape, and biological responses. Combined with experimental findings, these predictive models can jointly optimize the design of LNPs, formulations, and mRNA sequences to ensure their synergistic effects and enhance therapeutic outcomes.

The development of enterprises' LNP and mRNA design capabilities can play a synergistic role with the production advantages of upstream CXO companies.

At the product level, ESO-T01, a lentiviral vector-based product from EsoBiotec, currently shows promising clinical data.

On July 2 this year, Professor Mei Heng's team from Wuhan Union Hospital of China reported the clinical trial data of ESO-T01 in multiple myeloma patients in The Lancet. The clinical trial recruited four adult multiple myeloma patients. After treatment, the tumor of one patient disappeared within one month after injection, the tumor of another patient completely disappeared two months after treatment, and the other two patients achieved partial remission two months after injection. The clinical trial results indicate that ESO-T01 has potential therapeutic effects on relapsed or refractory multiple myeloma, which also means that in vivo CAR-T has moved from the concept validation and preclinical exploration stage to the early clinical stage.

Lentivirus vector route has a longer development history and better product stability; the mRNA-LNP route can avoid the risk of permanent genetic alterations, thus offering higher safety. Currently, research in the in vivo CAR-T field is proceeding simultaneously along both routes, and products from either route could potentially be the first to reach the market.

To address the uncertainty of technical routes, some companies have chosen to bet on dual strategies, with AbbVie being the most typical representative. Before acquiring Capstan, AbbVie had already partnered with Umoja on a lentiviral platform. In January 2024, AbbVie and Umoja announced a collaboration potentially worth up to $1.44 billion, granting AbbVie the right to use Umoja's proprietary VivoVec platform to develop multiple CAR-T cell therapy candidates. Umoja is also a key player in the in vivo CAR-T field, with its core VivoVec delivery platform being a lentiviral vector technology.

Through collaborations with Umoja and Capstan, AbbVie has simultaneously developed two technological approaches—lentiviral vectors and mRNA-LNP—mitigating the risk of falling behind in the in vivo CAR-T industry due to obstacles in a single technological pathway.

AbbVie's "double insurance" layout approach itself indicates that there is still significant uncertainty regarding the future development of the in vivo CAR-T industry. It remains to be seen which CRO/CDMO companies serving these investigational products will ultimately benefit from the prosperity of in vivo CAR-T.

Historical experience shows that emerging industries need revolutionary products to lead the way from the budding stage to a period of rapid growth. In the field of in vivo CAR-T, such revolutionary products must feature low treatment costs, clear clinical efficacy, and good safety. It still requires further research to determine which company's product has the potential to become this kind of revolutionary product.

Whether it's the lentivirus approach or the LNP approach, most of the current research is still in the early stages, and the actual business revenue it can bring to the upstream of the industry chain is not significant. It is only when products are advanced to later stages and clinical data is relatively positive that research and development companies will have greater business demands. "Substantial large-order revenues will only be gained by partners in the upstream of the industry chain," the person familiar with the in vivo CAR-T field told VCBeat.

In vivo CAR-T has now entered the preliminary clinical research stage, and commercialization scenarios are not yet mature. VCBeat will continue to track the industry's development and explore companies in the industrial chain with commercial value.