From CAR-T Pioneer to iPSC-CAR-NK Innovator: Dr. Richard Liqun Wang on Driving Original Innovation at Neukio Biotherapeutics

The former CEO of Fosun Kite, Wang Liqun, gained fame by launching the first CAR-T product in China. However, at the pinnacle moment when the product was approved, Wang Liqun unexpectedly left Fosun Kite and founded Xingyiang (Shanghai) Biotechnology Co., Ltd.

Externally, he claimed that the reason for his departure was "a lack of interest in operational work," but internally, he knew what mattered most was his optimism about the R&D prospects of CAR-NK. Since there were investors willing to back him, he had to seize this rare opportunity to innovate and engage in independent research and development.

Now, less than a year after leaving Fosun Kite, what is Wang Liqun's new company doing, and what new observations and thoughts does he have on the industry?

Recently, at the China Digital Oncology Industry High-Level Forum, VCBeat conducted an exclusive interview with Dr. Wang Liqun, founder of Xingyiang (Shanghai) Biotechnology Co., Ltd.

During an over one-hour interview, he spoke confidently and did not shy away from addressing some sensitive issues in the industry. For instance, while many believe that the approval pathway for domestic cell therapies has been cleared and that numerous China-developed CAR-T products will soon be approved for market, Wang Lixing soberly pointed out that regulators will not lower their standards just because the products are domestically produced. Promising cell therapy products in China still face significant uncertainties in the approval process.

In the interview, Wang Liqun mentioned "source innovation" more than ten times.

"The development status of China's biopharmaceutical industry is closely related to the strategic positioning of countless companies and the investment environment; choosing what targets and indications, whether it is original innovation or simply wanting to 'overtake on a curve,' adopt 'ready-made solutions,' seek quick wins, ultimately leading to internal competition."

Regarding the current "winter" or "involution" theories in the innovative drug industry, Wang Lixun clearly expressed his stance: the development of any industry experiences ups and downs. Setting aside the "winter" and "growing pains,"The true soul of biopharmaceuticals is innovation, and we must return to the essence of innovative drugs.

However, from the crowded PD-1 antibody drugs to CAR-CD19 and CAR-BCMA products in the cell therapy field, many pharmaceutical companies want to target certain validated (POC) targets and technologies, without positioning themselves for original innovation from the start. "How much of this is due to the founders, and how much is due to investor pressure?" Wang Lixing remarked.

At the peak of the PD-1 target's popularity, innovative pharmaceutical companies would feel embarrassed to even approach investors if their pipelines didn’t include PD-1. When everyone flocked to the CD-19, BCMA, and CD-22 targets, as long as a project was submitted for clinical trials, investors' money would already be in the account.

"When will you enter clinical trials?" Wang Liqun frankly admitted that this is a question every investor asks him.

However, short-term thinking will quickly lead to a highly repetitive and low-level industry, where no one is willing to pay for innovation, and the confidence of outstanding companies will undoubtedly be undermined.

Throughout his career, from the research and development of traditional drugs such as small molecules and large molecules, to later dedicating himself to pushing China's CAR-T cell therapy onto the market, and now transitioning to iPSC-CAR-NK, it can be said that Wang Lixing is always seeking opportunities for innovation.

Thanks to the understanding and favor of investors, Xingyiang (Shanghai) Biotechnology Co., Ltd. is currently not under significant financial pressure. However, Wang Liqun realizes that this is not a long-term solution, "We must make good use of this time and create some truly original innovations."

What is Original Innovation?In Wang Liqun's view, the essence lies in ideas. "Source innovation requires courage and team strength to explore, verify or falsify ideas that no one has thought of before, put them into practice, and finally confirm the efficacy through clinical data."

Where Do Original Ideas Come From?

Having been in the industry for a long time, Wang Liqun has a deep understanding of the pain points and shortcomings of cell therapy products. While working on CAR-T, he was already thinking about how to solve issues such as making it universal, mass-producible, and effective for treating solid tumors. By choosing the iPSC-CAR-NK technical route, what he values is its ability to meet the requirements of the next generation of immune cells: NK cells can serve as universal off-the-shelf products; NK cells can be differentiated from iPSCs to achieve consistent mass production; moreover, NK cells also have the potential for treating solid tumors.

He has long been following the American company Fate Therapeutics, which is currently at the forefront of the iPSC-CAR-NK field internationally. "When their Phase I clinical data came out, I took a look and thought it was pretty good. It gave me another reassurance, and I decided to go ahead with this."

Although Xingyiang (Shanghai) Biotechnology Co., Ltd. directly targets Fate, under the condition of similar underlying logic, "we are not copying them but conducting a more in-depth differential analysis. After screening out more suitable gene pathways and targets, we then edit and refine them, and develop different process solutions."

In less than a year since its establishment, Xingyiang (Shanghai) Biotechnology Co., Ltd. has been committed to creating a brand-new, universal, mass-producible "super NK cell" capable of treating solid tumors and endowing it with new functions. For each idea, Xingyiang has a small team dedicated to validating it separately, eventually integrating everything into the platform. In their view, this is where original innovation comes from.

Last year, Fosun Kite and Wuxi Juno's CAR-T products were successively approved for marketing. In March this year, the FDA also approved the marketing application in the United States for Legend Biotech's BCMA CAR-T product licensed to Johnson & Johnson. Does this mean that, for Chinese companies, the regulatory pathways for future CAR-T products in China and the United States have become clear?

Wang Liqun believes that the approval of the aforementioned products has laid the foundation for the drugability of autologous CAR-T products. However, due to customized production, the manufacturing processes of each product vary, making it difficult to generalize. Regulatory policies in China remain very strict and cautious.Facing corporate applications, the attitude of regulatory authorities remains on a case-by-case basis, and they will not relax approvals just because precedents have been set.

Even for Legend Biotech, which has partnered with Johnson & Johnson on a CAR-T product that is already on the market in the United States, Wang Liqun believes that its efforts to gain approval in China also face uncertainties. This depends on whether the same manufacturing processes and quality standards are adopted. Regulatory authorities will not easily lower their requirements, nor will they simply replicate the FDA's standards.

Following the approval and market launch of products by Fosun Kite and Wuxi Jumo through overseas technology transfer and domestic production, Wang Liqun hopes to see more domestically developed products from start to finish being launched in the market.If only the licensed-in products are approved for marketing while domestic products with potential face difficulties in getting to market, this would be detrimental to the development of the entire industry, and domestic companies may lose confidence.”

Wang Liqun observed and found that many cell therapy pharmaceutical companies in China have not truly recognized the R&D gap between China and international standards. Some companies believe that having sufficiently impressive IIT (Investigator-Initiated Trial) data will allow them to rise rapidly in the industry and gain quick approval. However, the reality is that for many years, they have remained in the clinical research stage, with no substantial progress toward marketing applications. This may also be related to an early lack of emphasis on standardized process development and quality control (CMC, Chemistry, Manufacturing, and Controls).

Currently, all approved CAR-T therapies are personalized and customized. The entire manufacturing cycle for producing autologous CAR-T cell therapy generally takes 2 to 4 weeks. Due to issues such as individual differences in cells, cell quantity, and cell quality, CAR-T faces certain homogeneity problems and the risk of production failure. Given the complex sample sources from different cancer patients, how to achieve efficient, standardized, and scalable production, and what technical means or solutions can be employed to meet anticipated commercial demands, are questions that CAR-T development companies commonly focus on, as well as issues that regulatory authorities consistently emphasize.

"The focus of regulatory authorities on the approval of CAR-T therapy is whether the product manufactured today is of the same quality as that produced yesterday or tomorrow. So, ultimately, it still comes down to process and quality control," emphasized Wang Lixing."Excellent preparation processes and product quality, along with good clinical safety and efficacy data, are the best path to approval."

The approval of autologous CAR-T products has removed some obstacles for the development of cell therapy, but Wang Liqun hopes that more companies will engage in more innovative research and development.To shift cell therapy from personalized approaches back to the traditional bioproduction process for universal application, which not only reduces costs but also ensures better product quality."The next step in product development should focus on expanding targets, breaking through solid tumors, and achieving the transition from autologous to off-the-shelf."

Although he chose the iPSC-CAR-NK technical route for his own entrepreneurial venture, Wang Lixing maintains a high level of attention toward emerging technical routes such as UCAR-T, TIL, and TCR-T.

Facing the limitations that autologous CAR-T has yet to overcome, UCAR-T attempts to address the customization challenges of autologous CAR-T by leveraging "off-the-shelf" features such as no need for matching, immediate use, and significantly reducing patient treatment cycles; more innovative cell therapies like TIL and TCR-T hope to achieve breakthroughs in treating solid tumors.

Currently, there are still technical difficulties in the development of UCAR-T. This is also why even Allogene, the fastest-moving company in this field, is still in the phase one clinical stage.

"Allogene can be considered one of the leading companies in developing universal CAR-T therapies, as they engineer primary cells. However, they have only edited two genetic pathways so far, which is likely close to the limit for primary cells. While this ensures a certain level of safety, the persistence of these cells in the body remains a key issue to address." Therefore, Wang Lixing believes that we still need time to wait for the progress of UCAR-T.

TIL therapy, with its advantages of higher safety, virtually no toxic side effects, the ability to specifically target multiple tumor antigens, and overcoming tumor heterogeneity, has become a highly anticipated treatment for solid tumors; the TCR-T field, due to its characteristics of a wide range of targetable antigens, good infiltration of solid tumors, and high sensitivity to antigens, has gradually gained momentum after attracting significant capital investment. However, only a very small number of these two therapies have entered the clinical validation stage.

Wang Liqun believes that,Compared with autologous CAR-T, TIL and TCR-T therapies are more customized.

"TILs are extracted from the patient's tumor tissue, and then T cells are expanded. However, each patient's situation is different. We need to analyze the reasons for T-cell infiltration in the tumor and determine its composition within the tumor. Because there is no clear single target cell, this makes it impossible for TILs to have a standard product like CAR-T that can describe and test their cell activity. Therefore, from the perspective of approval and regulation, it will be a challenge. The selection and preparation process of the standard product also need further clarification. In terms of cost, they face the same difficulties as autologous CAR-T."

CAR-NK, like TIL and TCR-T, is currently in its early stages. "Our startup has been around for a very short time, and many ideas are still in practice, requiring further validation. These validations cannot be achieved with a single experiment; strictly speaking, the real validation only comes when entering clinical trials and obtaining data."

In the future, iPSC-CAR-NK will face one challenge after another, but Wang Lixun knows that since there are investors willing to invest in Xingyiang (Shanghai) Biotechnology Co., Ltd., he must take on this responsibility, seize the opportunity to innovate, and pursue independent research and development.

As he has always emphasized, "If everyone focuses on short, quick, and easy products, China will never have original innovations.”