Decoding In Vivo CAR-T: From Technological Breakthroughs to Industrialization and Investment Logic

In recent years, in vivo CAR-T therapy has gradually transitioned from conceptual exploration to a more practically oriented R&D phase. Multinational pharmaceutical companies have begun to secure strategic positions through collaborations and mergers and acquisitions, while Chinese enterprises are simultaneously advancing their pipeline development and early-stage clinical exploration. Discussions surrounding this technological approach have shifted from “Is it feasible?” to “Is it worth investing in, and can it truly advance to clinical application?”

Unlike traditional ex vivo CAR-T therapy, which requires cell isolation, ex vivo expansion, and reinfusion, in vivo CAR-T utilizes delivery systems such as lipid nanoparticles (LNPs) or viral vectors to directly deliver CAR-related genetic information into the body, enabling T cells to undergo engineering modifications in situ. The core reason for its prominence lies not in the novelty of its technical format, but in its potential toReducing Manufacturing Complexity, Enhancing Treatment Accessibility, and Expanding Indications, alleviating the long-standing practical constraints faced by ex vivo CAR-T therapy.

It is against this backdrop that VCBeat has launched the roundtable live broadcast,Focusing on Technological Breakthroughs, Industrial Practices, and Investment Judgments in the In Vivo CAR-T SectorThe live stream was moderated by Kang Ting, Executive Director at GTJA Capital. It featured discussions with multiple industry and investment experts who have long tracked this field, including Kuang Yao, Managing Director at GTJA Capital; Zeng Xian, Co-founder and CEO of Yuanma Zhiyao; Xiao Lei, Co-founder of Stance Biotechnology; as well as Feng Xiao and Yi Liting, investment representatives from Shengjing Jiacheng Venture Capital and Daoyuan Capital, respectively. Drawing on their practical experience, the panelists engaged in dialogue to clarify a core question for the market: Whether in vivo CAR-T has entered a stage worthy of systematic investment and long-term tracking, despite the technology not yet having fully converged.

Ex vivo chimeric antigen receptor T-cell therapy (ex vivo CAR-T) has achieved commercialization, but itsBottlenecks in safety, indication expansion, and cost structure are gradually emerging., which has also become an important backdrop for the growing attention on in vivo CAR-T.

Kuang Yao, Managing Director at GTJA Investment, pointed out in her presentation that since the approval of the world’s first CAR-T product in 2017, a total of 14 CAR-T products have been launched globally as of June 2025, with seven approved in China. However, from the perspective of clinical practice, the therapeutic advantages of ex vivo CAR-T remain primarily concentrated in hematologic malignancies. Safety risks such as cytokine release syndrome (CRS) and neurotoxicity have not yet been fundamentally resolved, and response rates in solid tumors have remained persistently low. Meanwhile, the highly personalized manufacturing process has kept CAR-T therapies in a state of high cost and limited accessibility for an extended period.

She further noted that even though some domestically produced CAR-T products have been included in the national medical insurance or local supplementary health insurance schemes, the out-of-pocket burden for patients remains high. Although five products have recently been added to commercial insurance formularies, the potential for volume growth remains limited under the constraints of the current payment system and supply capacity. These practical limitations are prompting the industry to rethink the production and delivery models for CAR-T therapies.

In this context, in vivo CAR-T is regarded as a structural response to existing paradigms. Compared with ex vivo CAR-T, which requires complex processes including blood collection, ex vivo culture, expansion, and reinfusion, in vivo CAR-T directly modifies T cells within the body, holding promise for significantly reducing manufacturing costs and shortening the treatment cycle.

From a technical perspective, delivery systems constitute the core barrier for in vivo CAR-T therapy, currently comprising two main categories: lentiviral vectors and lipid nanoparticles (LNPs). The former offers advantages in durability of expression, while the latter holds greater potential in terms of safety and controllability. Different approaches involve differentiated trade-offs among efficacy, safety, and engineering feasibility.

From the perspective of R&D progress, the in vivo CAR-T pipeline has increased significantly since 2021, with more than 30 publicly disclosed projects under investigation by 2024. The global number of pipelines under development is expected to exceed 100 by 2025. In China, Legend Biotech’s vic100 (a CD19/CD20 dual-targeting therapy) is relatively advanced in its development and has initiated Investigator-Initiated Trials (IITs). However, overall, this field remains concentrated in the early stages of clinical development, both domestically and internationally.

Capital-market activity has further amplified this trend. Between 2024 and 2025, the total value of collaborations and M&A transactions related to in vivo CAR-T approached $10 billion, with multinational pharmaceutical companies such as AstraZeneca, AbbVie, and Gilead Sciences securing early positions through acquisitions and partnerships. In China, several companies, including Yuanma Zhiyao and Xinrui Pharma, completed financing rounds in the second half of 2025.

In Kuang Yao’s view,In vivo CAR-T is not a simple substitute for the ex vivo approach, but rather a systematic endeavor centered on cost, scalability, and the boundaries of indications.. If in vivo engineering can be achieved safely, controllably, and reproducibly, it means that the production system of cell therapy and patient coverage may be reshaped. This judgment also lays the foundation for subsequent discussions on technical pathways and industrial feasibility.

As industry consensus gradually takes shape,The focus of discussions on in vivo CAR-T has shifted from “whether it is feasible” to whether different technological approaches can achieve an engineered balance among safety, controllability, and efficacy.In pursuit of this goal, companies are adopting differentiated strategies to address the long-standing constraints of CAR-T therapy in terms of cost, scalability, and indication expansion.

Yuanma Zhiyao’s Co-founder and CEO, Zeng Xian, summarized the company’s strategy as transforming “one-person-one-drug” live-cell therapies into nucleic acid drugs capable of scalable manufacturing. To this end, Yuanma Zhiyao has chosen circular mRNA as the CAR expression vector and employs lipid nanoparticles (LNPs) for in vivo delivery.

Compared with linear mRNA, circular mRNA offers superior stability and sustained expression, making it better suited to meet the persistent expression requirements of CAR-T therapy. To enhance the efficiency of in vivo CAR-T cell generation, the company has further developed a targeted lipid nanoparticle (tLNP) system that enables selective delivery to T cells, thereby reducing the risk of off-target exposure. Currently, Yuanma Zhiyao has established an integrated technological platform comprising the “cmCAR Circular mRNA CAR Expression Platform” and the “CellectLNP Selective Delivery Platform,” along with a relatively stable manufacturing process, laying a solid foundation for subsequent clinical development.

Unlike non-viral approaches, Standcell Bio has chosen to focus on lentiviruses as its core platform, directly tackling the high-barrier challenge of in vivo CAR-T therapy for solid tumors. Co-founder Xiao Lei introduced the company’s CoupledCAR-T technical strategy, which introduces both CD19 CAR and solid tumor-targeting CAR into T cells. This approach leverages the strong activation signals triggered by CD19 CAR to enhance the expansion and functional efficacy of CAR-T cells targeting solid tumors.

Relevant clinical data indicate that, in the indication of relapsed/refractory colorectal cancer, the objective response rate (ORR) for the second dose cohort of Stance Bio’s autologous CAR-T product, GCC19CAR-T, in its domestic study was 50%, with a median overall survival (mOS) exceeding 26 months. In the U.S. Phase I clinical trial, 3 out of 6 patients in the second dose cohort achieved confirmed partial response (PR), and 1 patient achieved pathological complete response (pCR), resulting in an overall response rate (ORR) of 67%, which is significantly higher than that of previous standard-of-care treatments. Stance Bio has entered into an out-licensing collaboration with Lyell Immunopharma, a Nasdaq-listed company, featuring an upfront payment of USD 40 million and milestone payments exceeding USD 800 million.

Based on its clinically validated CoupledCAR-T platform technology for solid tumors, Stancee Bio has integrated a lentiviral in vivo delivery system and is expanding the application of in vivo CAR-T therapy in areas such as solid tumors and autoimmune diseases.

Despite differing paths, multiple guests have formed a highly consistent judgment:Safety remains the primary prerequisite for in vivo CAR-T.Xiao Lei pointed out that when viral vectors are applied in vivo, a systematic assessment of immune responses, off-target infection, and insertional mutagenesis risks is required. Zeng Xian added that although non-viral approaches avoid the issue of genomic integration, more clinical data are still needed to support their specificity of in vivo delivery, expression intensity, duration, and dose control.

As in vivo CAR-T continues to make substantial progress in engineering and early-stage clinical development, capital market interest in this sector is steadily intensifying. From intensive mergers and acquisitions by multinational pharmaceutical companies to forward-looking investments by domestic institutions, although the technological pathways have not yet been finalized, the industry has entered a critical phase where stakeholders “must monitor it and cannot afford to be absent.”

At the roundtable discussion, Feng Xiao from Shengjing Jiacheng Venture Capital stated that the concentrated moves by multinational corporations (MNCs) in the past two years were not driven by short-term sentiment, but rather represent an inevitable outcome of long-term industrial evolution. Since the implementation of Chapter 18A of the Hong Kong Stock Exchange listing rules in 2018 and the fifth set of listing standards on the STAR Market in 2019, exit channels for innovative drug assets have been opened up, allowing the Chinese market to continuously incubate a batch of early- to mid-stage projects with global value. The advantages of these assets are primarily reflected in clinical efficiency, engineering capabilities, and cost structures. They possess comprehensive strengths, particularly in advancing investigator-initiated trials (IITs), accelerating patient enrollment, and leveraging the maturity of the CXO ecosystem. Coupled with controllable R&D costs and high regulatory collaboration efficiency, these factors have made such assets a core focus for MNC mergers, acquisitions, and licensing deals.

Investment institutions generally believe that in vivo CAR-T represents a systematic integration of long-term technological accumulation, rather than a single-point breakthrough. Yiting Yi from Daoyuan Capital stated that her firm does not wait for technological pathways to fully converge before entering the market; instead, it focuses more on the technical differentiation, engineering certainty, and robustness of data demonstrated by companies in their early stages. “If one waits until all issues are thoroughly validated, the industrial landscape will have already taken shape.” The core role of capital is to provide phased support to help companies overcome key technological and clinical hurdles. On the corporate side, synergy between capital and industry is equally valued. Given the long development cycles and substantial investments required for innovative drug R&D, sustained capital support is a critical guarantee for advancing research and clinical trials. Furthermore, business development (BD) collaborations with industry partners not only validate a company’s technological platform but also bring in funding, while leveraging their global clinical and commercialization expertise to accelerate the internationalization of products.

Regarding the question of “whether it is time to place bets,” investors have offered judgments that lean more toward the operational level. Feng Xiao pointed out that current investment decisions do not hinge on betting on specific technical routes, but rather focus on the team’s execution capabilities in deconstructing complex problems, advancing engineering efforts, and achieving phased clinical validation. In his view, in vivo CAR-T is not suitable for a concentrated bet on a single approach; instead, it is better suited for long-term tracking, with incremental capital increases at key milestone nodes.

Yi Liting added from a longer-term industrial perspective that lentiviral vectors and LNP-based approaches may eventually form a relatively stable division of labor across different indications and application scenarios, akin to small-molecule or antibody drugs. Ultimately, the factors that will determine whether projects can advance to clinical development and commercialization remain those closely aligned with real-world healthcare systems, such as safety, patient adherence, and treatment cost.

Overall, capital’s stance on in vivo CAR-T is clear: it is not viewed as a short-term trend, but its potential to drive structural changes in the industry is highly valued.The betting window opened before the technology was finalized., the key lies in engaging with it rhythmically and grasping the core criteria for value judgment.

After in-depth discussion, the panelists reached a consensus: in vivo CAR-T is entering a development phase characterized by parallel pathways and a return to rational expectations.Lentiviral vectors and lipid nanoparticles (LNPs) will continue to advance in parallel, with no convergence on a single technology expected in the near term. Over the next two to three years, the industry’s focus will shift from conceptual innovation to the accumulation of clinical data and the refinement of engineering capabilities.

From the perspective of technological evolution, the two approaches have distinct focuses and offer complementary advantages. Leveraging a mature industrial chain and well-established durability of expression, lentiviral vectors are making steady progress in indications with high demands for sustained therapeutic efficacy, such as oncology. Meanwhile, the LNP approach, underpinned by its superior safety profile and potential for repeated dosing, is enabling broader exploration in autoimmune diseases. Furthermore, optimizations in foundational technologies, such as circular mRNA, are continuously addressing the limitation of transient expression associated with this platform.

On both clinical and commercial fronts, in vivo CAR-T therapy will continue to advance into more complex and challenging territories. Clinically, more projects will transition from exploratory studies to systematic clinical validation, with breakthroughs in complex indications such as solid tumors serving as key metrics for observation. Commercially, if safety and efficacy can be sufficiently demonstrated, its advantages in cost and accessibility will create new possibilities for payment systems; however, this process requires gradual support from clinical data and real-world evidence. The current landscape has completed technical validation. Although a unified pathway has yet to emerge, industry expectations have returned to rationality, with clear directions and well-defined opportunities. The field is now moving from proof-of-concept to a critical phase that tests engineering capabilities, clinical execution, and long-term endurance.

Addressing different stakeholders, the panelists offered pragmatic recommendations: enterprises should center their strategies on patient needs and clinical value, select suitable application scenarios based on their technological expertise, prioritize the development of clinical data and CMC (Chemistry, Manufacturing, and Controls) systems, and navigate the challenges of long-cycle R&D through strategic business development (BD) partnerships and financing; investment institutions should ground their decisions in the fundamentals of technology and clinical development timelines, providing long-term support to teams with sustained innovation capabilities, rather than chasing short-term trends.

As delivery technologies mature and clinical data continue to emerge, in vivo CAR-T therapy is poised to carve out a distinct niche in the field of cell therapy. This sector, which demands patience, professional judgment, and long-term investment, holds potential value that warrants sustained attention from the industry.