The In Vivo CAR-T Race Heats Up: Experts Discuss Paths Forward

In  Vivo CAR-T, which directly reprograms T cells inside the body,  significantly simplifies treatment procedures and reduces costs. It is  regarded as a key solution to improving the accessibility of cell  therapies and has become a widely discussed topic in recent years. The  approach has also gained strong interest from investors. For example, in  March 2025, AstraZeneca acquired EsoBiotec for RMB 7 billion. More  recently, on June 30, 2025, AbbVie announced the acquisition of the  aforementioned Capstan Therapeutics for $2.1 billion.

As  pharmaceutical giants such as Pfizer and Novartis expand their  investments in LNP delivery technology, and Bayer's AskBio explores AAV  vector applications, a competitive landscape in in vivo CAR-T therapy is  rapidly taking shape. Breaking through bottlenecks in delivery  efficiency, safety, and large-scale production has become a shared  challenge facing all participants in the field.

During  the aforementioned dialogue, experts explored technological pathways in  the in vivo cell therapy sector—a topic of significant industry  interest. From the choice between viral and non-viral delivery systems  to strategies for expanding indications and challenges in scalable  manufacturing, they analyzed the current landscape and future trends of  the field from multiple perspectives.

Notably,  Chinese companies are accelerating their strategic deployment in the in  vivo CAR-T sector. Advances such as METiS Technologies' research on  extrahepatic delivery demonstrate that innovative Chinese enterprises  are rapidly catching up in this domain and striving to secure a position  in the global cell therapy market. On September 16, METiS Technologies  officially launched its self-developed NanoForge platform—reportedly the  world’s first AI-driven nanodelivery platform. The platform enables a  closed-loop process spanning molecular generation, property prediction,  AI-guided wet-dry lab iteration, lipid formulation design and  optimization, and final dosage form determination. Through continuous  learning and evolution, NanoForge is poised to continually expand the  data barrier in nanodelivery technology.

In  the field of in vivo CAR-T technology, the selection of delivery  systems has become a primary challenge. Current major technical  approaches include LNP delivery, viral delivery, and physical delivery  methods. The targeted lipid nanoparticle (tLNP) technology utilized by  Capstan Therapeutics represents a prominent non-viral delivery pathway,  while viral delivery systems based on lentivirus or AAV also maintain  broad support within the research community.

Professor  Hamideh Parhiz stated at the CSGCT meeting that when examining all  these platform technologies, the focus is always on efficiency. The  translational potential of all technologies depends on their efficiency,  and efforts are made to compare new technologies with existing  achievements to determine if they are more efficient, less efficient, or  compatible.

Academician  Zhang Dan added from an industrial perspective: "Different technologies  may be better suited for different indications. Whether in chronic  diseases, malignant tumors, or anti-aging fields, each is likely to have  its own optimal matching solution."

METiS  Technologies adopts the same tLNP approach as Capstan Therapeutics, and  based on the NanoForge platform, it has developed three core solutions:  AiLNP (AI-driven Nucleic Acid Delivery System Design Platform), AiRNA  (AI-driven mRNA Sequence Design Platform), and AiTEM (AI-driven Small  Molecule Formulation Design Platform).

As  of now, METiS Technologies has a library of over 10 million lipid  structures and 100,000 data points available for model training. It has  achieved a breakthrough in targeted LNP delivery to 8 identified organs  or tissues in the human body, including the liver, lungs, immune organs,  heart, muscles, tumors, central nervous system, and gastrointestinal  tract. The company holds a total of more than 100 authorized patents and  filed patent applications. Additionally, METiS Technologies has  successfully developed over 10 pipeline projects, generated 7  preclinical candidate drugs, and is advancing 4 clinical projects in  parallel, with its most advanced pipeline having reached the pre-NDA  stage.

It is further  understood that METiS Technologies has obtained T cell-targeted LNP data  that surpasses that of many global benchmark In Vivo CAR-T companies.  This indicates that its technology can more efficiently engineer T  cells, unlock the potential of CAR-T therapy, and better empower the  research and development of innovative drugs in China. In the future,  devastating autoimmune diseases such as lupus are expected to be  addressed through METiS Technologies' T cell-targeted LNP. This  technology enables in vivo T cell reprogramming to precisely eliminate  the abnormally activated B cells that cause disruptions, essentially  pressing a "factory reset button" for the humoral immune system and  restoring it to a clean, initial state.

Dr.  Chris Lai pointed out: "At present, antibody-conjugated targeted lipid  nanoparticles (tLNP) mainly focus on delivery to the blood and lymphatic  systems."

Regarding the  question of how to overcome the potential challenges of tLNP technology  in delivering to hard-to-reach organs such as the kidneys in the future,  Professor Hamideh Parhiz acknowledged the existence of this challenge  and proposed a solution: "In some tissues, when delivery barriers exist,  a dual-targeting strategy may need to be designed: the first is  semi-specific targeting, and the second requires an additional layer of  targeting to help cross these barriers."

As  for this challenging issue, it is understood that METiS Technologies  intends to address it through a three-layer strategy. The first layer is  passive targeting. The second layer focuses on its ongoing research to  decode how plasma proteins in the body bind to these materials and which  organs the bound complexes are subsequently delivered to. The third  layer is active targeting, which achieves organ-specific targeted  delivery by conjugating with antibodies. Notably, promising progress  toward overcoming the challenge has been observed across all three  layers.

Beyond technical pathways, the strategy for selecting indications is also a focal point of industry attention.

Capstan  Therapeutics has opted to enter the market by targeting autoimmune  diseases rather than the traditional oncology treatment space, a  strategy that has drawn attention within the industry. Professor Heng  Mei, Chief Physician of the Department of Hematology at Union Hospital,  Tongji Medical College, Huazhong University of Science and Technology,  also posed a question to Hamideh Parhiz: Why choose cardiovascular  diseases or autoimmune diseases over malignant tumors? Is this decision  related to the use of non-viral delivery systems?

It  is reported that in July 2025, the Union Hospital, Tongji Medical  College, Huazhong University of Science and Technology announced that  the first-in-human trial of the in-vivo CAR-T therapy ESO-T01 developed  by the Belgian company EsoBiotec was completed by the team of Professor  Mei Heng. This achieved clinical success in treating multiple myeloma  with the in-vivo chimeric antigen receptor T-cell (CAR-T) therapy,  marking new progress in blood tumor cell therapy. Four refractory  multiple myeloma patients completed the lowest-dose group trial.

In  response to Professor Heng Mei's question, Professor Hamideh Parhiz  stated: "We have observed significant therapeutic effects in these  patients, which is why we chose to enter the market from this area.  However, we certainly plan to expand into the field of hematological  oncology in our next phase."

Regarding  the choice between viral and non-viral vector delivery systems,  Professor Hamideh Parhiz holds the view that it depends on specific  application scenarios. Sometimes a retroviral system may be more  suitable, while in other cases tLNP could be better—there is no single  approach that can serve as a universal solution. "For example, when it  comes to the elimination of certain cells, if a non-viral system can do  this effectively—such as achieving deep B-cell depletion—even though it  is based on an mRNA system (which is transient), if it can accomplish  the task, we may be more inclined to use a non-viral system rather than a  viral one."

In  the view of Dr. Chris Lai, delivery efficiency is absolutely  critical. Currently, the depletion of B cells is used as a marker to  gauge whether a technology is effective, but for applications in the  field of oncology, the standards would be significantly higher.

Moreover,  during the discussion, Dr. Lai emphasized an often-overlooked  issue: many developers of novel delivery systems neglect a core  challenge—scalability. When complex solutions are used to tackle  technical problems, considerations around CMC (Chemistry, Manufacturing,  and Controls) and clinical translation feasibility are frequently  underestimated. These issues may pose serious challenges in the future.

Having  experience in operating both a CDMO and a clinical CRO, Academician  Zhang Dan has observed a variety of exploratory directions, such  as circular RNA, AAV-based in vivo CAR-T, and other highly innovative  novel ideas. He believes that ultimately, different technologies may be  better suited for different indications—whether in chronic  diseases, malignant tumors, or the anti-aging field—each potentially  having its own optimal matching solution.

When asked  whether large-scale production of antibody or nanobody conjugation  technology can ensure high-quality control, Professor Hamideh Parhiz  noted that during earlier discussions on tLNP technology, many were  skeptical, arguing that adding an antibody layer would be highly  challenging without successful clinical translation. However, she  consistently maintained that the key lies in advancing the technology  toward practical implementation.

"Indeed, when we refer to tLNP-mRNA technology, its essence lies in the integration of a 'targeting module' with an 'LNP-mRNA delivery platform'. Notably, as the core technology behind COVID-19 mRNA vaccines, LNP-mRNA has been  administered to billions of people worldwide, with its manufacturing  process rigorously validated. Thus, the feasibility of this  technological pathway has been unequivocally demonstrated," emphasized  Professor Hamideh Parhiz.

Meanwhile, Professor Hamideh  Parhiz also emphasized that if a technology's complexity exceeds current  capabilities, its necessity must be carefully weighed—the key lies in  defining clear technical objectives, as the choice of any technological  pathway must align with actual demands.

Dr. Chris Lai  further illustrated this point by citing current antibody-conjugated  tLNP and viral vector technologies as proven effective approaches with  broad commercial potential. Even if next-generation technologies  eventually replace certain existing solutions, they will not negate the  value of current systems—much like how monoclonal antibodies were never  replaced by bispecific antibodies, but instead jointly advanced the  field.

It is understood that Chinese enterprises are also accelerating their layout in the in vivo CAR-T field.

Academician  Zhang Dan revealed that his team in China is responsible for the  production of lentivirus-based in vivo CAR-T, and has also initiated IIT  in China.

This  information indicates that Chinese enterprises have entered a  substantive phase in their layout within the in vivo CAR-T field.  Developments such as METiS Technologies' research progress in  extrahepatic delivery, as well as the layout of CDMO enterprises like  Hillgene in the in vivo CAR-T manufacturing sector, all show that China  is accelerating its efforts to catch up with the international advanced  level.

In the view of the  industry, a true breakthrough in in vivo CAR-T technology may await the  emergence of new materials and technologies, or the iterative upgrading  of existing technologies. However, there is no doubt that once someone  can break through the bottlenecks in delivery efficiency, safety, and  large-scale production, it will inevitably reshape the competitive  landscape of the cell therapy market.

From a global  perspective, although Chinese enterprises started relatively late in  their layout in the in vivo CAR-T field, they are expected to achieve a  "corner overtaking" in this domain by virtue of their accumulated  experience in the gene therapy and cell therapy sectors, as well as  their rapidly iterative technological capabilities.

The  progress of innovative enterprises such as METiS Technologies indicates  that China's innovation vitality in the in vivo CAR-T technology field  should not be underestimated. With more capital and talents flocking  into this field, China is expected to become a crucial market for the  research, development and application of global in vivo CAR-T  technology.

Ultimately,  the success of in vivo CAR-T technology depends not only on the  sophistication of the technology itself, but more importantly on its  ability to achieve large-scale production and control costs—thereby  allowing more patients to benefit from this revolutionary therapeutic  technology.