In Vivo CAR-T as future infrastructure: Dr. Lu Zhou's vision of Santo Therapeutics amidst China's coming biotech shakeout

While most biopharmaceutical companies are still grappling with the customized production, high costs, and long waiting periods of ex vivo CAR-T therapies, a new race has quietly begun – moving the "cell factory" directly into the human body, allowing T cells to be reprogrammed autonomously in the bloodstream.

This is the vision painted by in vivo CAR-T technology. By 2025, this field is gradually gaining momentum, with some industry observers predicting that hundreds of companies in China will enter the in vivo CAR-T arena.

Dr. Lu Zhou, founder of Santo Therapeutics, believes this will be the "next oncology field worth going all-in on" after PD-1. In this arena, Santo aims to become the company achieving "the lowest dosage and highest safety standards."

Dr. Zhou has keenly identified China's unique advantages: the current "engineer dividend" and substantial "clinical resources dividend." When vast clinical needs are paired with innovative business models, they can transform into powerful drivers for R&D. The current vibrancy in cross-border BD transactions precisely reflects international recognition of the value of China's clinical data and its R&D efficiency.

"It takes 2-3 years to initiate clinical trials in the U.S., whereas in China, IIT studies can complete dose exploration in just 3-6 months. Overseas biotech companies can't afford such long timelines, so they have to turn to Chinese data," Dr. Zhou remarked, describing China's "speed advantage" — one of the key reasons he chose to return to China to start his business.

Dr. Lu Zhou, founder of Santo Therapeutics. Iamge Provided by the interviewee

Where does Santo Therapeutics' confidence in reaching the finish line first come from? It likely stems from four factors that create a "half-step lead" in the race: Santo has managed to reduce the effective dose of in vivo CAR-T, lower production costs, and accelerate clinical timelines. Moreover, its fifth-generation lentiviral vector platform shifts from ex vivo cell modification to in vivo modification, bypassing the complexity, challenges, and high costs associated with ex vivo processes — significantly cutting treatment expenses.

In the field of innovative drug development, it is notoriously difficult to simultaneously achieve rapid clinical translation, broad product applicability, and substantial commercial profits—a clear logical paradox.

Pursuing rare diseases allows a company to reach the finish line first, leveraging well-defined pathogenesis, faster clinical trials, and regulatory incentives. However, this path ultimately leads to the reality of a limited market size. Conversely, targeting major diseases with large patient populations implies a long, arduous, and uncertain path to market, where attractive commercial returns remain a distant prospect.

"If you insist on simultaneously achieving the goals of rapid market entry, large patient populations, and high profitability, you will only corner yourself," Dr. Zhou explained, commenting on the industry's prevailing anxiety. To resolve this dilemma, Santo Therapeutics' strategy is to "get on the bus first, then change seats" – swiftly entering the clinic via rare diseases, and subsequently transferring the refined vector platform, honed in this process, to broader fields like autoimmunity and oncology.

This is precisely what Santo is putting into practice: targeting schwannomatosis caused by NF2 gene mutations. With a global incidence of 1 in 25,000, it is classified as a rare disease, yet it perfectly represents the monogenic loss model that gene therapy is best suited to address.

In February 2025, Santo Therapeutics initiated the world's first IIT for "in vivo lentiviral delivery of the NF2 gene," in collaboration with the Cancer Hospital of the Chinese Academy of Medical Sciences. Multiple patients have already received dosing in this study.

According to data from Maximize Market Research, the global neurofibromatosis treatment market is projected to reach $27.06 billion USD (approximately RMB 144.9 billion) by 2029, growing at a compound annual growth rate (CAGR) of 13.3%. Furthermore, corporate financial reports indicate that selumetinib, an existing targeted therapy for NF1, generated $331 million in sales in 2023 with a CAGR of 72%, yet its use is limited by the need for lifelong dosing, drug resistance, and side effects such as paronychia.

"If we can achieve tumor volume stabilization and symptom improvement through a one-time in vivo gene replacement therapy, it would effectively transform lifelong medication into a single curative treatment. This holds strong appeal for both payers and healthcare systems," noted Dr. Zhou Lu. He pointed out that once the "small gate" of rare disease review is pushed open, it may lead to a much broader field of application.

More critically, the NF2 program has also served as a testing ground for Santo Therapeutics to validate its lowest effective dose.

"For every order of magnitude we reduce the dose, the cost drops by approximately 70%, and toxicity is significantly decreased," revealed Dr. Zhou Lu. He shared that repeated validation in primary models has shown that even this minimal effective dose alone is sufficient to restore Merlin protein expression within tumor cells and potently inhibit tumor growth.

"If we can replicate this number in humans, we will possess the industry's lowest efficacy threshold. This 'formula' can later be replicated in areas like autoimmunity and solid tumors."

Why is Santo Therapeutics firmly committed to in vivo CAR-T? Its advantages are multidimensional, particularly in terms of treatment accessibility and cost control.

Another major appeal of in vivo CAR-T lies in its ultimate simplification of the treatment process. It eliminates the multi-week steps required for ex vivo CAR-T—such as cell collection, shipping, manufacturing, expansion, and quality control—and allows patients to forgo lymphodepleting chemotherapy. This achieves a true "treat upon arrival" model, reducing the treatment timeline from weeks to mere hours. For critically ill patients, this difference can be a matter of life and death.

"Ex vivo CAR-T is like 'handicraft production,' while in vivo CAR-T is an 'assembly line,'" summarized Dr. Zhou. He explained that in vivo CAR-T compresses the complex steps of ex vivo CAR-T—cell separation, activation, expansion, quality testing, and reinfusion—into batch production and a single intravenous injection. This efficiency gain could potentially increase the number of treatable patients by up to 70%, significantly broadening therapeutic accessibility.

The choice of technological pathway remains a critical challenge in the maturation of in vivo CAR-T therapy.

The debate over optimal vectors has persisted within the industry for some time. Dr. Zhou Lu emphasizes that the merits of specific vectors, such as lentiviral vectors (LV) or adeno-associated viruses (AAV), should not be evaluated in isolation. Instead, a comprehensive assessment must integrate factors including the specific disease indications, target cell types, and the intended delivery strategy.

Taking Santo's dedicated focus on lentiviral vectors (LV) as an example, they demonstrate high transfection efficiency for dividing cells like T cells. Furthermore, as LV is derived from the Human Immunodeficiency Virus (HIV), its long-term co-evolution with the human immune system suggests an inherent biological rationale for its interaction.

Dr. Zhou Lu explained that lentiviruses support repeat dosing to enhance or sustain efficacy, a strategy currently being explored in clinical trials by several companies, with preliminary data confirming its feasibility.

In contrast, while Adeno-associated virus (AAV) holds an advantage in transducing non-dividing cells, it faces challenges such as potential neutralization by pre-existing immunity and severe safety concerns observed in some high-dose cases. Similarly, Lipid Nanoparticles (LNP) contend with issues of transient expression, limited durability of effect, and challenges in integration efficiency.

Dr. Zhou Lu firmly believes that the ultimate endpoint for all therapies will trend toward "in vivo" approaches. While ADCs can be described as attaching a guided missile to a drug, in vivo cell engineering is equivalent to establishing an "arsenal" within the body. The future of vector technology lies in its ability to achieve true "in vivo drug manufacturing" – that is, guiding the body's own cells to continuously, even lifelong, produce therapeutic proteins or CAR constructs.

Based on this conviction, Santo Therapeutics is focusing on building foundational platform capabilities in in vivo CAR-T and gene therapy. The company is constructing an integrated cell and gene therapy platform that encompasses viral vector engineering, precise targeting of tissues and organs, and immune activation with transcriptional regulation.

Guided by this philosophy, Santo Therapeutics has anchored its strategy on two core principles: an unwavering commitment to the "in vivo" pathway, and the continuous pursuit of the "lowest effective dose."

Identifying the minimum effective dose not only signifies enhanced safety but also demonstrates the potential to achieve best-in-class status in specific therapeutic areas. Achieving the "lowest dose in the industry" within safe thresholds represents a paradigm shift from the traditional dose-escalation approach based on the maximum tolerated dose (MTD). Dr. Zhou Lu disclosed that existing clinical data have shown their low-dose regimen can reduce toxicities such as cytokine release syndrome (CRS) to significantly lower levels.

Santo Therapeutics' strategic vision extends beyond NF2, with autoimmune diseases like systemic lupus erythematosus (SLE) positioned as its next therapeutic frontier. Given the typically indolent progression of autoimmune conditions, the required therapeutic dose is projected to be substantially lower. By leveraging non-integrating lentiviral vectors, this approach could potentially challenge existing antibody therapies in both safety profile and cost-effectiveness.

The company is executing a dual-track strategy: advancing its NF2 program toward IND submission while simultaneously initiating R&D for new pipelines. This effort is supported by advanced tools including microfluidics and AI modeling to optimize both manufacturing processes and clinical trial design.

When low-cost, scalable gene therapies become a reality, and when GMP production of viral or non-viral vectors achieves standardization, treatment accessibility will no longer be constrained by manufacturing complexity or price. Dr. Zhou Lu likens this strategy to "first building the hospital parking lot – the patients will then find their own way." The approach aims to eliminate all barriers except for payment capability, thereby clearing the path for widespread adoption of therapies.

Facing the potential homogenization of hundreds of in vivo CAR-T companies in China, Dr. Zhou expresses both calm and optimism: "After the industry endures its great shakeout, only a few will remain standing." In his assessment, the ultimate form of in vivo CAR-T will evolve into a foundational infrastructure within biomedicine, built through multi-stakeholder collaboration. He views this intense market frenzy not just as a passing trend, but as a historic opportunity for Chinese biotech. With in vivo CAR-T, China has the potential to achieve global leadership and break through every perceived "impossibility."